Open Ph.D. positions
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CALL FOR APPLICATIONS
PHD PROGRAMME AT INSTITUTE OF PHYSIOLOGY CAS
The applicant must complete an:
Please select at least one choíce from the the list of available positions. The topics for Ph.D. studies are divided by specialization.
Application deadline: 15.3. 2025
We also invite you to participate in Day of Physiology and Medicine for Undergraduate Students 2025, which can be attended in person or online. The event takes place on 20 February. A recording of the lectures will also be available after the event.
Neuroscience
Molecular regulation of Mitochondrial Transport and Neural Development
Laboratory name: Molecular Neurobiology
Supervisor (email): Martin Balastik, Ph.D., (Martin.Balastik@fgu.cas.cz)
PhD project: Molecular regulation of Mitochondrial Transport and Neural Development
Mitochondrial transport is essential for nearly all cellular processes but is particularly critical in neurons, where it ensures energy distribution and availability within their long, polarized processes. Dysregulation of microtubule-based mitochondrial transport in neurons has been implicated in numerous neurodevelopmental and neurodegenerative disorders. Mitochondrial transport is tightly regulated by adaptor proteins, and in humans, mutations in the adaptor protein TRAK1 have been linked to severe developmental and epileptic encephalopathies (DEE). Through a large-scale whole-genome and exome sequencing project on DEE patients, we have identified several new TRAK1 and TRAK2 gene variants, underscoring the critical role of both genes in neural development and disease. Additionally, we have generated mouse models with various mutations in TRAK1 gene that exhibit severe developmental encephalopathy, and premature lethality.
In this PhD project, the selected student will investigate the effects of TRAK1 and TRAK2 gene variants identified in DEE patients on mitochondrial transport and neural development. Specifically, the project will involve: In vitro studies – characterizing the impact of the identified variants on mitochondrial transport in cultured neurons. In vivo analysis – using in utero electroporation to study the role of these variants in cortical development. Comparative studies – performing phenotypic analyses of TRAK1 and TRAK2 mutant mice to assess their roles in neuron migration, brain connectivity, and function. The project will employ advanced techniques, including microfluidic chambers for neuron cultures, molecular biology methods, and imaging-based assays for mitochondrial transport. The project is supported by funding from the Czech Science Foundation and from project Exceles Neur-IN ensuring comprehensive financial and technical support. This project offers a unique opportunity to elucidate the role of TRAK proteins in mitochondrial transport and their broader implications in neural development and disease.
Candidate’s profile (requirements):
We are seeking outstanding self-motivated candidates with master’s degree or equivalent in molecular biology, biochemistry, physiology, medicine or related fields, or those expecting to obtain their degree this year. Candidates must be fluent in English. Experience with in vivo models (mouse, rat) as well as with in vitro cell cultures and molecular biology techniques are advantage.
References:
- Maimon R, et al, A CRMP4-dependent retrograde axon-to-soma death signal in amyotrophic lateral sclerosis EMBO J, 2021, Sep 1;40(17):e107586
- Ziak J, et al, CRMP2 mediates Sema3F-dependent axon pruning and dendritic spine remodeling, EMBO Rep, 2020 Mar 4;21(3):e48512.
Multidisciplinary study of neurodevelopmental disorders associated with variants in NMDA receptor genes
Laboratory: Cellular Neurophysiology
Head of the Laboratory: Prof. L. Vyklický MD, PhD, DSc
Supervisors: Aleš Balík, PhD (ales.balik@fgu.cas.cz) or Tereza Smejkalová, PhD (tereza.smejkalova@fgu.cas.cz)
PhD Project: Multidisciplinary study of neurodevelopmental disorders associated with variants in NMDA receptor genes
N-methyl-D-aspartate receptors (NMDARs) are synaptic glutamate receptors with a key role in synaptic plasticity. NMDAR function is therefore critical for the development of neural circuits and for their ability to process and store information. In recent years, changes in GRIN genes encoding NMDAR subunits have been detected in patients with neurodevelopmental disorders typically manifested by developmental delay, intellectual disability, and often some form of epilepsy. Over 700 different disease-associated GRIN gene variants have been identified so far, including 9 found in pediatric patients in the Czech Republic, but how these variants may be involved in disease etiology and what therapeutic interventions may be beneficial for individual patients remains poorly understood.
The selected PhD candidate will work on one of the sub-topics: (1) Using bioinformatics approaches and molecular biology techniques we will investigate the possible link between GRIN gene variants and the genetic background of patients and to study the effects of variants on the regulation of other GRIN genes and the possible presence of specific genetic compensatory mechanisms. (2) Using biochemistry and immunofluorescence microscopy we will assess the effects of variants on NMDAR assembly and subcellular localization. (3) Using patch-clamp electrophysiology and live-cell Ca2+ imaging we will study NMDAR function, synaptic transmission and plasticity, and network activity in neuronal preparations expressing individual patient GRIN gene variants. Results of this work will improve our understanding of the complex nature of GRIN disorders and help guide precision therapy approaches suitable for individual GRIN patients.
Candidates’ Profile (requirements):
We are seeking motivated candidate/s with a master’s degree or equivalent in genetics, bioinformatics, molecular biology, biochemistry, physiology, medicine or related fields, or a student expecting to obtain their degree this year. Experience with molecular biology techniques, cell culture, animal models, microscopy and/or work with bioinformatics tools is an advantage.
References:
Candelas Serra et al. (2024) Characterization of Mice Carrying a Neurodevelopmental Disease Associated GluN2B (L825V) Variant. J Neurosci. 44(31):e2291232024.
Korinek et al. (2024) Disease-Associated Variants in GRIN1, GRIN2A and GRIN2B genes: Insights into NMDA Receptor Structure, Function, and Pathophysiology. (Review) Physiol Res. 73(Suppl 1):S413-S434.
Kysilov et al. (2024) Disease-associated nonsense and frame-shift variants resulting in the truncation of the GluN2A or GluN2B C-terminal domain decrease NMDAR surface expression and reduce potentiating effects of neurosteroids. Cell Mol Life Sci. 81(1):36.
Kysilov et al. (2022) Pregnane-based steroids are novel positive NMDA receptor modulators that may compensate for the effect of loss-of-function disease-associated GRIN mutations. Br J Pharmacol. 179(15):3970-3990.
Smejkalova et al. (2021) Endogenous neurosteroids pregnanolone and pregnanolone sulfate potentiate presynaptic glutamate release through distinct mechanisms. Br J Pharmacol. 178(19):3888-3904.
Hirschfeldova et al. (2021) Evidence for the Association between the Intronic Haplotypes of Ionotropic Glutamate Receptors and First-Episode Schizophrenia. J Pers Med. 11(12):1250.
Mechanisms of selective modulation of individual subtypes of muscarinic receptors
Laboratory name: Neurochemistry
Supervisor (email): Jan Jakubík, jan.jakubik@fgu.cas.cz
PhD project: Mechanisms of selective modulation of individual subtypes of muscarinic receptors
Altered muscarinic signalling is frequently involved in neurological and psychiatric diseases as well as diseases of internal organs. To target a particular condition, selective modulation of individual muscarinic subtypes is necessary to avoid side effects. High homology of the orthosteric binding site among all muscarinic subtypes makes a finding of orthosteric ligands that bind selectively to individual muscarinic subtypes virtually unattainable. Allosteric ligands modulate binding of orthosteric ligands and functional response to agonists from less-conserved sites on the receptor. Dualsteric ligands employ both orthosteric and allosteric sites. The aim of this project is structure-guided development of novel selective allosteric and dualsteric ligands.
Candidate’s profile (requirements):
We are seeking highly motivated independent candidate with a master’s degree or equivalent in pharmacology, biochemistry, molecular biology or related fields, or those expecting to obtain their degree this year. Essentially, candidate should be fluent in English and willing to travel to collaborating laboratories abroad to learn new techniques required for this project. Experience with in vitro cell culture, molecular biology techniques and basic programming skills are an advantage.
References:
- Nelic D et al. Agonist-selective activation of individual G-proteins by muscarinic receptors. Sci Rep ;14(1):9652. doi:10.1038/s41598-024-60259-4
- Jakubík J et al. The operational model of allosteric modulation of pharmacological agonism. Sci Rep 2020;10(1):14421. doi: 10.1038/s41598-020-71228-y
- Randáková A and Jakubík J, Functionally selective and biased agonists of muscarinic receptors. Pharmacol Res. 2021;169:105641. doi: 10.1016/j.phrs.2021.105641
- Randáková A, et al, Novel long-acting antagonists of muscarinic ACh receptors. Br J Pharmacol. 2018; 175(10):1731-1743. doi: 10.1111/bph.14187
Nicotinic acetylcholine receptors in prefrontal neuronal populations and their role in the control of ASD-like behavioral symptoms
Laboratory name: Laboratory of Cholinergic Signaling
Supervisor (email): Helena Janickova, MD, PhD (helena.janickova@fgu.cas.cz)
PhD project: Nicotinic acetylcholine receptors in prefrontal neuronal populations and their role in the control of ASD-like behavioral symptoms
Nicotinic acetylcholine receptors (nAChRs) are implicated in autism spectrum disorders (ASD) and other neuropsychiatric disorders, but it is challenging to use them as an effective therapeutic target. One of the reasons is their widespread distribution in the brain and thus the difficulty in controlling them selectively in circuits and neurons where needed. The present project aims to determine whether the selective modulation of nAChRs in specific neuronal types is more effective in the control of ASD-like behavioral symptoms in mice compared to non-selective nicotinic modulation. To this aim, students will analyze the expression of the most common nAChR subtypes in individual neuronal populations in the mouse prefrontal cortex using RNAscope and FISH. They will then manipulate the expression of the receptors in specific neurons by shRNA and CRISPR. Finally, the effect of these manipulations will be examined by behavioral testing in automated touchscreen-equipped operant boxes, and the effect on neuronal activity will be assessed by imaging techniques.
Candidate’s profile (requirements):
(brief description of the required background of the applicants, i.e. education, title, languages, etc.)
We are looking for a self-motivated candidate with a master’s degree in molecular biology, biochemistry, physiology, medicine or related fields. Experience with cloning, viral vectors, calcium imaging and/or handling mice is advantageous. The successful candidate is supposed to spend a certain period of time in his/her PhD studies in a collaborating laboratory(ies). Therefore, the willingness to travel and fluency in English is essential.
References:
- Abbondanza A, Ribeiro Bas I, Modrak M, Capek M, Minich J, Tyshkevich A, Naser S, Rangotis R, Houdek P, Sumova A, Dumas S, Bernard V, Janickova H.: Nicotinic acetylcholine receptors expressed by striatal interneurons inhibit striatal activity and control striatal-dependent behaviors. J Neurosci. 2022, 42: 2786-2803.
- Urushadze A, Janicek M, Abbondanza A, Janickova H.: Timed sequence task: a new paradigm to study motor learning and flexibility in mice. eNeuro. 2023, 10: ENEURO.0145-23.2023.
- Abbondanza A, Urushadze A, Alves-Barboza AR, Janickova H.: Expression and function of nicotinic acetylcholine receptors in specific neuronal populations: Focus on striatal and prefrontal circuits. Pharmacol Res. 2024, 204: 107190.
Neuronal-type-specific targeting of nAChRs using a pair of nitroreductase and masked nicotinic ligands
Laboratory name: Laboratory of Cholinergic Signaling
Supervisor (email): Helena Janickova, MD, PhD, helena.janickova@fgu.cas.cz
PhD project: Neuronal-type-specific targeting of nAChRs using a pair of nitroreductase and masked nicotinic ligands
Nicotinic acetylcholine receptors (nAChRs) are implicated in autism and other neuropsychiatric disorders, but it is challenging to use them as a therapeutic target. One of the reasons is their widespread distribution in the brain and thus the difficulty in controlling them selectively in circuits and neurons where needed. The present project aims to develop a new approach for the neuronal-type-specific targeting of nAChRs using a pair of an engineered bacterial enzyme nitroreductase and a nicotinic ligand masked with a nitroaryl group. We collaborate with a lab of organic synthesis on the preparation of the masked ligands. The PhD student will test the nicotinic activity of the masked compounds in vitro and their distribution by fluorescence in vitro and in vivo. The selective unmasking of the compounds and their ability to alter nicotinic expression will be ultimately tested in vivo.
Candidate’s profile (requirements):
(brief description of the required background of the applicants, i.e. education, title, languages, etc.)
We are looking for a self-motivated candidate with a master’s degree in molecular biology, biochemistry, physiology, medicine or related fields. Experience with organic synthesis, neuronal cultures, viral vectors and/or handling mice is advantageous. The successful candidate is supposed to spend a significant time of his/her PhD studies in a collaborating laboratory(ies). Therefore, the willingness to travel and fluency in English is essential.
References:
- Abbondanza A, Ribeiro Bas I, Modrak M, Capek M, Minich J, Tyshkevich A, Naser S, Rangotis R, Houdek P, Sumova A, Dumas S, Bernard V, Janickova H.: Nicotinic acetylcholine receptors expressed by striatal interneurons inhibit striatal activity and control striatal-dependent behaviors. J Neurosci. 2022, 42: 2786-2803.
- Urushadze A, Janicek M, Abbondanza A, Janickova H.: Timed sequence task: a new paradigm to study motor learning and flexibility in mice. eNeuro. 2023, 10: ENEURO.0145-23.2023.
- Abbondanza A, Urushadze A, Alves-Barboza AR, Janickova H.: Expression and function of nicotinic acetylcholine receptors in specific neuronal populations: Focus on striatal and prefrontal circuits. Pharmacol Res. 2024, 204: 107190.
Neuroinflammation and pain
Laboratory name: Pain Research
Supervisor (email): Jiri Palecek, M.D., Ph.D., jiri.palecek@fgu.cas.cz
PhD Project: Neuroinflammation and pain
The main research interest of our department is to study mechanisms of pain and to explore new possibilities of pain treatment, especially in chronic states. Our experimental work is concentrated on the modulation of nociceptive information at the spinal cord level that is the first relay center between the periphery and higher brain areas. Our goal is to study these modulatory mechanisms in order to improve therapy for pain conditions such as neuropathic and cancer related pain. This project will be focused on the role of neuroinflammation in modulation of synaptic transmission and chronic pain development. Lately we are interested in the role of TRPV1 receptors, cannabinoids, endogenous lipids, opioids and inflammatory cytokines in this process. In our research we use mainly electrophysiological, optogenetic, OMICS analysis, functional imaging, immunohistochemical, molecular and behavioral methods. In collaboration with clinics we aim to study human pathology in pain patients. Our research is supported by several ongoing grant projects.
Candidate Requirements: The candidate should have a Masters’ degree in biological, medical or chemical sciences, or be due to complete their studies in this academic year. Experience in physiology, neurophysiology, cell biology, molecular biology or electrophysiology techniques would be an advantage. Candidates should be fluent in Czech or English.
References:
Li Y, Adamek P, Zhang H, Tatsui CE, Rhines LD, Mrozkova P, Li Q, Kosturakis AK, Cassidy, Harrison,.Cata,P. Sapire,K. Zhang,H. Kennamer, R. M. Jawad, A.B. Ghetti, Yan, J., Paleček, J. Dougherty, P. M. The Cancer Chemotherapeutic Paclitaxel Increases Human and Rodent Sensory Neuron Responses to TRPV1 by Activation of TLR4. J Neurosci. 2015;35(39):13487-13500. IF=6.3
Nerandzic V, Mrozkova P, Adamek P, Spicarova D, Nagy I, Palecek J. Peripheral inflammation affects modulation of nociceptive synaptic transmission in the spinal cord induced by N-arachidonoylphosphatidylethanolamine. British Journal of Pharmacology 2018, 175, 2322-2356. IF = 6.8
Adamek P, Heles M, Palecek J, Mechanical allodynia and enhanced responses to capsaicin are mediated by PI3K in paclitaxel model of peripheral neuropathy. Neuropharmacology. 2019,146:163-174. IF=4.3
Heleš M, Mrózková P, Šulcová D, Adámek P, Špicarová D, Paleček J. Chemokine CCL2 prevents opioid-induced inhibition of nociceptive synaptic transmission in spinal cord dorsal horn. Journal of Neuroinflammation. 2021; 18(1)); 279 . IF = 9.6
Uchytilová; E, Špicarová D, Paleček J. Hypersensitivity Induced by Intrathecal Bradykinin Administration Is Enhanced by N-oleoyldopamine (OLDA) and Prevented by TRPV1 Antagonist. Int. J. Mol. Sci. 2021; 22(7)); 3712. IF = 6.2
Adamek, M. Heles, A. Bhattacharyya, M. Pontearso, J. Slepicka, J. Palecek. Dual PI3K-δ/γ Inhibitor Duvelisib Prevents Development of Neuropathic Pain in Model of Paclitaxel-Induced Peripheral Neuropathy. Journal of Neuroscience. 2022 Mar 2; 42(9):1864-1881. IF=6.7
Spicarova D, Nerandzic V, Muzik D, Pontearso M, Bhattacharyya A, Nagy I and Palecek J. Inhibition of synaptic transmission by anandamide precursor 20:4-NAPE is mediated by TRPV1 receptors under inflammatory conditions. Frontiers in Mol. Neuroscience 2023, 16:1188503,1-11, 2023, IF = 6.2.
Circadian disruption in non-neural brain tissue studied by integrative omics and luminescence microscopy
Laboratory name: Biological rhythms
Supervisor (email): Martin Sládek (martin.sladek@fgu.cas.cz)
PhD project: Circadian disruption in non-neural brain tissue studied by integrative omics and luminescence microscopy
The project will focus on non-neural brain structures, particularly on choroid plexus (ChP), a crucial tissues for brain homeostasis and the pathophysiology of neuropsychiatric disorders, due to it being the main source of cerebrospinal fluid (CSF) in brain ventricles. ChP contains a robust circadian clock that rhythmically regulates its physiological functions. ChP clock is highly sensitive to circadian clock disruption (CD) by light, mistimed feeding or glucocorticoids. We hypothesize that CD impairs the CSF production, composition and brain waste clearance via the ChP clock and that timed feeding regime can ameliorate its negative impact.
We will use transgenic mice of both sexes with circadian reporter to study the effects of CD on ChP organotypic explants with bioluminescence microscopy. We will compare control, experimental (CD) and intervention (CD with restricted feeding) groups of mice, sampling CSF and ChP around the clock and analyzing circadian rhythms by lipidomics, metabolomics and transcriptomics. We will employ single-cell RNAseq (Chromium) to identify cell-specific changes in RNA levels in response to CD. We will also analyze locomotor activity and blood-CSF barrier permeability. PhD student will be trained among other things in tissue culture, molecular biology methods and bioinformatics.
Candidate’s profile (requirements):
Background in molecular biology, genetics, or cell biology; Masters (Mgr.) degree; English; familiarity with at least one of the following: either molecular biology methods (PCR), or cell culture (sterile work), or bioinformatics, or Python/R.
References:
SLADEK, M., P. HOUDEK, J. MYUNG, K. SEMENOVYKH, T. DOCKAL AND A. SUMOVA The circadian clock in the choroid plexus drives rhythms in multiple cellular processes under the control of the suprachiasmatic nucleus. Fluids Barriers CNS, May 27 2024, 21(1), 46. IF 7.3
DRAPSIN, M., T. DOCKAL, P. HOUDEK, M. SLADEK, K. SEMENOVYKH AND A. SUMOVA Circadian clock in choroid plexus is resistant to immune challenge but dampens in response to chronodisruption. Brain, Behavior, and Immunity, Mar 2024, 117, 255-269. IF 15.1
SLADEK, M., J. KLUSACEK, D. HAMPLOVA AND A. SUMOVA Population-representative study reveals cardiovascular and metabolic disease biomarkers associated with misaligned sleep schedules. Sleep, Jun 13 2023, 46(6), zsad037. IF 5.6
GREINER, P., P. HOUDEK, M. SLADEK AND A. SUMOVA Early rhythmicity in the fetal suprachiasmatic nuclei in response to maternal signals detected by omics approach. PLoS Biology, May 2022, 20(5), e3001637. IF 9.8
Metabolism
Mesenteric adipose tissue as part of the intestinal barrier in the progression of MASLD
Laboratory name: Laboratory of Adipose Tissue Biology
Supervisor (email): Olga Horáková, PhD. (olga.horakova@fgu.cas.cz)
PhD project: Mesenteric adipose tissue as part of the intestinal barrier in the progression of MASLD
The pathophysiology of metabolic steatotic liver disease (MASLD) includes obesity with excessive accumulation of hepatic fat and, in later stages, metabolic dysfunction of hepatocytes, inflammation and fibrosis with subsequent risk of hepatocellular carcinoma. The progression of MASLD is also stimulated by the external environment, not only by dangerous pathogens, but also by essentially harmless molecules such as food-derived antigens. The well-known protection of the liver from the outside world is provided by the multi-layered intestinal barrier. We hypothesize that mesenteric adipose tissue (mWAT) is an integral part of this barrier.
The aims of this project are 1) to define the role of mWAT in small intestinal barrier function during the development of MASLD and 2) to explore the potential of omega-3 fatty acids (primarily phospholipids) to improve ileal barrier function. We will use a mouse model of diet-induced MASLD (including germ-free mice), functional analysis of adipose and intestinal tissue, flow cytometry, metabolipidomic analysis, and bioinformatics. Understanding the role of mWAT in the progression of MASLD will help to develop new treatments.
Candidate’s profile (requirements):
We are looking for highly motivated PhD student with an MSc. degree or equivalent in life sciences or related fields, or those who expect to graduate this year. Previous experience with animal experiments, flow cytometry or bioinformatics is an advantage.
References:
Horáková, Olga – Kroupová, Petra – Bardová, Kristina – Burešová, Jana – Janovská, Petra – Kopecký, Jan – Rossmeisl, Martin Metformin acutely lowers blood glucose levels by inhibition of intestinal glucose transport. Scientific Reports 2019, 9(Apr 16)), 6156. doi: 10.1038/s41598-019-42531-0
Kroupová; Petra – van Schothorst; E. M. – Keijer; J. – Bunschoten; A. – Vodička; Martin – Irodenko; Ilaria – Oseeva; Marina – Žáček; P. – Kopecký; Jan – Rossmeisl; Martin – Horáková; Olga Omega-3 Phospholipids from Krill Oil Enhance Intestinal Fatty Acid Oxidation More Effectively than Omega-3 Triacylglycerols in High-Fat Diet-Fed Obese Mice. Nutrients. 2020; 12(7)); 2037. doi: 10.3390/nu12072037
Mitrović; Marko – Sistilli; Gabriella – Horáková; Olga – Rossmeisl; Martin Omega-3 phospholipids and obesity-associated NAFLD: Potential mechanisms and therapeutic perspectives. European Journal of Clinical Investigation. 2022; 52(3)); e13650. doi: 10.1111/eci.13650
The role of mitochondrial phospholipase A2γ and mitochondrial redox and lipid signaling in selected tissues
Laboratory name: Mitochondrial Physiology
Supervisor (email): Martin Jabůrek, Ph.D. (martin.jaburek@fgu.cas.cz)
PhD project: The role of mitochondrial phospholipase A2γ and mitochondrial redox and lipid signaling in selected tissues
Mitochondria are dynamic, energy-transforming, and signaling organelles that have become the most studied organelle in the biomedical sciences. One of the long-term goals of our laboratory includes uncovering mechanisms in which mitochondrial oxidants, lipids, and lipid-derived electrophiles participate in redox homeostasis and cellular signaling. This includes the convergence of mitochondrial lipid and redox signaling and the role of mitochondrial phospholipases.
The aim of the PhD project is to characterize the role of mitochondrial phospholipase A2γ and mitochondria-derived lipids in selected tissues and cell types. Our current focus is on brown adipocytes, specialized in non-shivering thermogenesis, and pancreatic β-cells, responsible for insulin secretion, but this project can involve other tissues and cell types. Our laboratory uses a wide range of biochemical and biophysical approaches, including models of isolated reconstituted iPLA2y, isolated mitochondria, isolated brown adipocytes and pancreatic islets, and in vivo models using genetically modified mice. There are plenty of opportunities for motivated students.
Candidate’s profile (requirements):
We are seeking outstanding self-motivated candidates with bachelor’s degree or master’s degree in biochemistry, physiology, molecular biology, or related fields, or those expecting to obtain their degree within the year. Candidates should be fluent in English. Experience with biochemical and molecular biology techniques is an advantage.
References:
Jabůrek M., et al. (2024) Mitochondria to plasma membrane redox signaling is essential for fatty acid β-oxidation-driven insulin secretion. Redox Biol. 75:103283
Ježek P., et al. (2024) Mitochondrial Physiology of Cellular Redox Regulations. Physiol Res. 73(S1): S217-S242
Průchová P., et al. (2022) Antioxidant role and cardiolipin remodeling by redox-activated mitochondrial Ca2+-independent phospholipase A2γ in the brain. Antioxidants 11(2):198
Effect of genetic factors and perinatal programming on individual mechanisms of non-shivering thermogenesis in mice
Laboratory name: Adipose Tissue Biology, Institute of Physiology of the Czech Academy of Sciences
Supervisor: Ing. Petra Janovska, PhD (petra.janovska @fgu.cas.cz; ORCID 0000-0002-6154-2175)
PhD project: Effect of genetic factors and perinatal programming on individual mechanisms of non-shivering thermogenesis in mice
Our recent results obtained in mice suggested a possibility to reduce obesity through adaptive enhancement of non-shivering thermogenesis (NST) in skeletal muscle. This PhD project focuses on the characterization of the: (i) role of genetic background of mice on muscle NST and its subsequent effect on obesity; (ii) mechanisms responsible for the permanent setting of muscle NST levels during a critical time window shortly after birth, as indicated by our unpublished results; and (iii) in vitro effects of candidate compounds on energy expenditure in muscle satellite cells derived from mice differing in capacity for muscle NST. The project will employ: (i) long-term experiments in mice with in vivo phenotyping of whole-body metabolism; (ii) utilization of omics techniques and associated data analyses; and (iii) application of bioanalytical methods in vitro. This research will deepen understanding of muscle NST and its potential as a novel therapeutic target for obesity treatment. By exploring the genetic and developmental factors influencing NST, as well as testing effects of selected compounds in muscle cells, this project may pave the way for innovative obesity interventions.
Candidate’s profile (requirements):
We are seeking highly motivated, creative candidates with Master degree or equivalent in molecular biology, biochemistry, physiology, medicine, pharmacology or related disciplines, or students expecting to obtain their degree this year. Experience with bioinformatics or application of basic statistical methods in biology are advantage.
Relevant publications:
Janovska P, Zouhar P, Bardova K, Otahal J, Vrbacky M, Mracek T, Adamcova K, Lenkova L, Funda J, Cajka T, Drahota Z, Stanic S, Rustan A.C, Horakova O, Houstek J, Rossmeisl M and Kopecky J. 2023 Impairment of adrenergically-regulated thermogenesis in brown fat of obesity-resistant mice is compensated by non-shivering thermogenesis in skeletal muscle. Molecular Metabolism 69: 101683.
https://doi.org/10.1016/j.molmet.2023.101683
Bardova K, Janovska P, Vavrova A, Kopecký J, Zouhar P. 2024 Adaptive induction of nonshivering thermogenesis in muscle rather than brown fat could counteract obesity. Physiological Research 73:S279-S294 https://doi.org/10.33549/physiolres.935361
Deciphering Lipid Metabolism in Cancer: Integrative Approaches in Metabolomics, Fluxomics, and Metabolic Engineering
Laboratory name: Metabolism of Bioactive Lipids
Supervisor (email): Ondrej Kuda (ondrej.kuda@fgu.cas.cz)
PhD project: Deciphering Lipid Metabolism in Cancer: Integrative Approaches in Metabolomics, Fluxomics, and Metabolic Engineering
This PhD project investigates the rewiring of lipid metabolic pathways in cancer using an integrative approach combining metabolomics, fluxomics, metabolic engineering, and in silico modeling. The research aims to deconvolute complex lipid metabolic pathways through metabolic flux analysis and stable isotope tracer studies, supported by Python-based data processing pipelines and advanced computational modeling.
The study incorporates experimental work, including cancer cell culture models and in vivo mouse models, to validate findings and quantify metabolic fluxes under physiological and pathological conditions. In silico simulations of lipid metabolism will be used to predict pathway behavior and identify potential intervention points. Machine learning approaches will aid in biomarker discovery and the prediction of metabolic vulnerabilities, offering insights into the mechanisms driving cancer progression and potential therapeutic targets.
This interdisciplinary project bridges computational biology, biochemistry, and experimental cancer research, contributing to our understanding of lipid metabolism and the development of precision strategies for metabolic engineering and cancer therapy.
The work will be conducted at the IPHYS CAS. The work is financially secured in terms of material and full time position.
Candidate’s profile (requirements):
The prerequisites for success are knowledge of programming languages for working with data (Python), basic biochemistry (metabolites, pathways, cellular compartments), and an overview of omics disciplines. Previous experience with cell cultures and mouse experiments is an advantage.
References:
Lopes et al. Metabolomics atlas of oral 13C-glucose tolerance test in mice. Cell Rep. 2021 Oct 12;37(2):109833. doi: 10.1016/j.celrep.2021.109833
Vondrackova et al. LORA, Lipid Over-Representation Analysis Based on Structural Information. Anal Chem. 2023 Aug 29;95(34):12600-12604. doi: 10.1021/acs.analchem.3c02039
Integrated approaches for metabolomics and lipidomics - data-driven insight using machine learning and biochemical networks
Laboratory name: Metabolism of Bioactive Lipids
Supervisor (email): Ondrej Kuda (ondrej.kuda@fgu.cas.cz)
PhD project: Integrated approaches for metabolomics and lipidomics – data-driven insight using machine learning and biochemical networks
This PhD project focuses on advancing the integration of metabolomics and lipidomics to unravel the regulation of complex biochemical networks and metabolic dynamics. The study leverages state-of-the-art data processing techniques, computational tools, and machine learning algorithms to extract actionable insights from large-scale fluxomics datasets. Python-based pipelines will be developed to standardize data preprocessing, feature extraction, and analysis while incorporating machine learning models for network clustering, classification, and predictive modeling of metabolic pathways.
The project emphasizes cross-disciplinary approaches, blending expertise in biochemistry, computational biology, and data science to create robust tools for understanding metabolic systems. Outcomes are expected to contribute to personalized medicine, metabolic engineering, and systems biology, offering novel methodologies and software frameworks for the scientific community.
The work will be conducted at the IPHYS CAS, where the metabolomics and proteomics service laboratory is located. The work is financially secured in terms of material and full time position.
Candidate’s profile (requirements):
The prerequisites for success are knowledge of programming languages for working with data (Python), basic biochemistry (metabolites, pathways, cellular compartments), and an overview of omics disciplines. The candidate should be fluent in English and willing to travel to collaborating laboratories abroad.
References:
Lopes et al. Metabolomics atlas of oral 13C-glucose tolerance test in mice. Cell Rep. 2021 Oct 12;37(2):109833. doi: 10.1016/j.celrep.2021.109833
Vondrackova et al. LORA, Lipid Over-Representation Analysis Based on Structural Information. Anal Chem. 2023 Aug 29;95(34):12600-12604. doi: 10.1021/acs.analchem.3c02039
https://github.com/IPHYS-Bioinformatics
Studies of mitochondrial lipotoxic dysfunction in pancreatic cancer
Laboratory name: Mitochondrial Physiology
Supervisor (email): Katarína Smolková (katarina.smolkova@fgu.cas.cz)
PhD project: Studies of mitochondrial lipotoxic dysfunction in pancreatic cancer
Inhibition of mitochondrial metabolism in non-adipose tissues results in triglyceride (TG) synthesis and accumulation in lipid droplets (LDs). This is caused by inhibited import of activated fatty acids (FAs) into mitochondria, which leads to redirection of FAs into LDs and protects from the deleterious effects of FA oxidation (Gotvaldová et al 2024, PMID: 38532464). We aim to investigate mechanisms that regulate the utilization of FAs in mitochondria as opposed to TG synthesis and how this is reflected in mitochondrial lipotoxicity.
We will use cell knockout cell lines partially defective in TG synthesis, and also knockout of the mitochondrial enzyme CRAT, which is able to induce pancreatic tumorigenesis via epigenetic regulations. In this project, we aim to identify a lipotoxic culprit responsible for mitochondrial damage that affects mitochondrial function and cell survival. Using multi-omics approaches, we will identify metabolic and gene signatures associated with mitochondrial oxidative and lipotoxic damage. We will also focus on post-translational modifications in knockout models.
The goal of the project is to identify crosstalk mechanisms between cellular compartments, namely mitochondria, peroxisomes and LDs, focusing on FA dynamics within them. Our work should link the metabolic effects of mitochondrial oxidative processes to anabolic metabolism and reveal additional mechanisms of metabolic signaling in cancer cells.
Candidate’s profile (requirements):
(brief description of the required background of the applicants, i.e. education, title, languages, etc.)
We request a candidate with the experience in cell/molecular biology or biochemistry. Bacground in cancer biology is preferred, but not required.
References:
BCAA metabolism in pancreatic cancer affects lipid balance by regulating fatty acid import into mitochondria. Gotvaldová K, Špačková J, Novotný J, Baslarová K, Ježek P, Rossmeislová L, Gojda J, Smolková K Cancer & Metabolism 2024; 12, 10.
Pancreatic cancer: branched-chain amino acids as putative key metabolic regulators? Rossmeislová L, Gojda J, Smolková K. Cancer & Metastasis Reviews 2021; 40, 1115–1139.
Studying the role of bone marrow adipocytes in mouse models of obesity: impact of sex
Laboratory: Molecular Physiology of Bone
Supervisor (email): Michaela Tencerová, Ph.D. (michaela.tencerova@fgu.cas.cz)
PhD project: Studying the role of bone marrow adipocytes in mouse models of obesity: impact of sex dimorphism
Obesity is a worldwide health problem associated with increased risk of fractures and bone damage, which are accompanied by higher bone marrow adipose tissue (BMAT) accumulation. With obesity, the function of key building blocks, bone marrow stromal cells (BMSCs), changes towards higher BMAT accumulation, which is influenced by diet and sexual dimorphism. Men and women have unique nutritional needs based on physiological and hormonal changes over the lifespan, which may contribute to the impact on the primary function of BMSCs and thus the prevalence of bone fractures in men and women. However, the precise molecular mechanism underlying sex-specific differences in the molecular properties of BMSCs and the pathophysiology of bone loss is not well understood. The aim of this project is to investigate the effect of different dietary interventions (e.g. different fatty acid, amino acid content) on BMAT expansion and molecular properties of BMSCs in mouse models with different susceptibility to obesity (obesity-prone C57BL/6 mice and obesity-resistant A/J mice). The study will also investigate how these factors affect bone quality, cellular metabolism of BMSCs with a particular focus on sexual dimorphism.
The project will employ mouse phenotyping methods (analyzing of metabolic parameters- i.e. glucose tolerance, body composition measured by DEXA, bone microstructure using different bioimaging methods microCT, contrast-enhanced CT, BMAT evaluation), isolation of primary BMSCs and applying several molecular methods (gene expression, protein analysis, differentiation capacity, bioenergetics etc.). Project will be conducted at the Institute of Physiology of CAS in collaboration with excellent laboratories abroad. The basic PhD scholarship will be supported by the national and international grants.
Candidate’s profile (requirements):
We are seeking highly motivated, creative candidates with MSc degree or equivalent in molecular biology, biochemistry, physiology, medicine, pharmacology or related disciplines, or students expecting to obtain their degree this year. Experience with molecular biology techniques and in vitro cell culture methods are advantage.
References:
Benova A., et al. Novel thiazolidinedione analog reduces a negative impact on bone and mesenchymal stem cell properties in obese mice compared to classical thiazolidinediones. Mol Metab. 2022 Nov;65:101598. doi: 10.1016/j.molmet.2022.101598. Epub 2022 Sep 11
Tencerova M, et al. Metabolic programming of bone marrow stromal stem cells determines lineage- differentiation fate. Bone Res. 2019 Nov 14;7:35. doi: 10.1038/s41413-019-0076-5.
Tencerova M, et al. Obesity associated hypermetabolism and accelerated senescence of bone marrow stromal stem cells suggest a potential mechanism for bone fragility. Cell Rep. 2019 May 14;27(7):2050-2062.e6. doi: 10.1016/j.celrep.2019.04.066.
Tencerova M, et al. High fat diet-induced obesity promotes expansion of bone marrow adipose tissue and impairs skeletal stem cell functions in mice. J Bone Miner Res. 2018 Feb 14. doi: 10.1002/jbmr.3408.
Tencerova M, Kassem M. The Bone Marrow-Derived Stromal Cells: Co mitment and Regulation of Adipogenesis. Front Endocrinol (Lausanne). 2016 Sep 21;7:127.
Role of efficiency of muscle contraction and non-shivering thermogenesis in protection against cold and obesity
Laboratory name: Adipose Tissue Biology
Supervisor: Petr Zouhar, PhD (petr.zouhar@fgu.cas.cz; ORCID 0000-0002-1111-9109)
PhD project: Role of efficiency of muscle contraction and non-shivering thermogenesis in protection against cold and obesity
The excess of energy intake over energy expenditure leads to the development of obesity and its associated health complications. Important components of energy expenditure are the thermogenic mechanisms primarily designed to maintain a stable body temperature, but possibly also useful in ensuring energy homeostasis. In addition to brown adipose tissue, shivering and possible non-shivering mechanisms in skeletal muscle contribute significantly to thermogenesis. Our research to date has revealed significant variability in the extent of utilization of each mechanism among different inbred strains of laboratory mice, and possible link between higher involvement of muscle non-shivering thermogenesis and resistance to obesity.
As part of the PhD project, the student will test the hypothesis that non-shivering thermogenesis in skeletal muscle is facilitated by 1) the formation of respiratory chain supercomplexes, which influence the efficiency of ATP generation, and 2) the expression of the peptide sarcolipin, which regulates calcium transport across the sarcoplasmic reticulum membrane. This will be done by phenotyping genetically modified mouse strains with increased formation of respiratory supercomplexes, with particular emphasis on their susceptibility to obesity and on muscle contraction efficiency assessed by ex vivo measurements of contraction force, and energy expenditure during exercise and cold exposure assessed by indirect calorimetry.
Candidate’s profile (requirements):
We are seeking highly motivated, creative candidates with MSc degree or equivalent in molecular biology, biochemistry, physiology, medicine, pharmacology or related disciplines, or students expecting to obtain their degree this year. Experience with animal experiments, cell cultures, bioinformatics, and/or biostatistics are considered an advantage.
References:
Janovska P, Zouhar P, Bardova K, Otahal J, Vrbacky M, Mracek T, Adamcova K, Lenkova L, Funda J, Cajka T, Drahota Z, Stanic S, Rustan A.C, Horakova O, Houstek J, Rossmeisl M and Kopecky J. 2023 Impairment of adrenergically-regulated thermogenesis in brown fat of obesity-resistant mice is compensated by non-shivering thermogenesis in skeletal muscle. Molecular Metabolism 69: 101683.
https://doi.org/10.1016/j.molmet.2023.101683
Bardova K, Janovska P, Vavrova A, Kopecký J, Zouhar P. 2024 Adaptive induction of nonshivering thermogenesis in muscle rather than brown fat could counteract obesity. Physiological Research 73:S279-S294 https://doi.org/10.33549/physiolres.935361
In vivo and in vitro characterization of mechanisms of muscle non-shivering thermogenesis
Laboratory name: Adipose Tissue Biology
Supervisor (email): Mgr. Kristina Bardová, Ph.D. (kristina.bardova@fgu.cas.cz)
PhD project: In vivo and in vitro characterization of mechanisms of muscle non-shivering thermogenesis
Energy homeostasis reflects a balance between energy intake and energy expenditure. In birds and mammals, control of energy expenditure is important for stable body temperature, and in all the organisms for regulation of body weight. Thus, energy expenditure represents a target for the prevention and treatment of obesity and associated diseases, which is a major problem for the health care systems in affluent societies.
The objective of this project is to explore in detail the mechanisms of muscle non-shivering thermogenesis, with a particular focus on calcium futile cycling facilitated by SERCA/sarcolipin interaction and respirátory supercomplex composition. Specifically, we will focus on (i) the role of sympathetic nervous system in the regulation of muscle non-shivering thermogenesis; (ii) in vitro model of pharmacological activation of futile calcium cycling in muscle cells; and (iii) the measurement of metabolism of isolated muscles and muscle fibres. The student will gain experience with the following methodology: immunohistochemistry and 3D evaluation, holotomographic microscope, indirect calorimetry, and high-resolution respirometry.
The student will be involved in the project under the supervision of Mgr. Kristina Bardova, Ph.D. In the first year of the program, student will be expected to acquire the necessary skills to complete the project. She will mainly focus on the introduction of methodology. Since the second year of the program, she will perform experiments on genetically modified models with manipulated muscle SERCA/sarcolipin system and respirátory supercomplex composition, both in vitro and in vivo. In the fourth year of the project, the results will be published in impacted journals.
Candidate’s profile (requirements):
Candidates must hold a Master of Science degree in a relevant discipline, such as biology, physiology, or a related field. Proficiency in either English or both English and Czech is essential, with the ability to communicate effectively in either English or in both languages.
References:
DOI: 10.1016/j.molmet.2023.101683
Accordion název
Cardiovascular Physiology
Biomimetic nanofibers supporting chronic wound healing
Laboratory name: Laboratory of Biomaterials and Tissue Engineering
Supervisor (email): Elena Filova, PhD, elena.filova@fgu.cas.cz
MSc project: Biomimetic nanofibers supporting chronic wound healing
Chronic non-healing wounds have become a major health problem in the elderly population, often in association with diabetes. Chronic wounds show impaired cell proliferation, excessive extracellular matrix degradation, lower concentrations of growth factors, higher oxidative stress, etc. However, new bioactive materials are being developed that can stimulate chronic wound healing.
The aim of this study is to develop nanofiber dressings with a bioactive component and evaluate their ability to stimulate various cellular processes necessary for wound healing. It will include the effect of nanofibers on various skin cells such as keratinocytes, fibroblasts, endothelial cells and stem cells in mono- and co-cultures in vitro. The study will include the evaluation of cell adhesion, proliferation, differentiation/maturation, migration and ECM production in 2D and 3D environments, as well as the development and practical use of a chronic wound model in vitro.
Candidate’s profile (requirements):
The candidate should have a bachelor’s degree from a university with a focus on natural sciences, biomedical engineering, or a related field and be able to communicate in English.
References:
1. Táborská J, Blanquer A, Brynda E, Filová E, Stiborová L, Jenčová V, Havlíčková K, Riedelová Z, Riedel T. PLCL/PCL Dressings with Platelet Lysate and Growth Factors Embedded in Fibrin for Chronic Wound Regeneration. Int J Nanomedicine. 2023 Feb 3;18:595-610. doi: 10.2147/IJN.S393890. eCollection 2023.
2. Blanquer A, Kostakova EK, Filova E, Lisnenko M, Broz A, Mullerova J, Novotny V, Havlickova K, Jakubkova S, Hauzerova S, Heczkova B, Prochazkova R, Bacakova L, Jencova V. A novel bifunctional multilayered nanofibrous membrane combining polycaprolactone and poly (vinyl alcohol) enriched with platelet lysate for skin wound healing. Nanoscale. 2024 Jan 25;16(4):1924-1941. doi: 10.1039/d3nr04705a.
3. Adrian E, Treľová D, Filová E, Kumorek M, Lobaz V, Poreba R, Janoušková O, Pop-Georgievski O, Lacík I, Kubies D. Complexation of CXCL12, FGF-2 and VEGF with Heparin Modulates the Protein Release from Alginate Microbeads. Int J Mol Sci. 2021 Oct 28;22(21):11666. doi: 10.3390/ijms222111666.
4. Filova E, Blanquer A, Knitlova J, Plencner M, Jencova V, Koprivova B, Lisnenko M, Kostakova EK, Prochazkova R, Bacakova L.Nanomaterials (Basel). 2021 Apr 13;11(4):995. doi: 10.3390/nano11040995. The Effect of the Controlled Release of Platelet Lysate from PVA Nanomats on Keratinocytes, Endothelial Cells and Fibroblasts.
Enhancement of vascularized bone tissue formation using functionalized diamond scaffolds and electric stimulation
Laboratory name: Laboratory of Biomaterials and Tissue Engineering
Supervisor (email): Elena Filova, PhD, elena.filova@fgu.cas.cz
PhD project: Enhancement of vascularized bone tissue formation using functionalized diamond scaffolds and electric stimulation
Guaranteeing workplace:
- Institute of Physiology of the Czech Academy of Sciences, Department of Biomaterials and Tissue Engineering (Dr. Elena Filová)
- Institute of Physics of the Czech Academy of Sciences, Department of Semiconductors (Dr. Štěpán Potocký
Bone defect healing and long-term function of the regenerated bone tissue are influenced by many factors, such as bone density, vascularization, defect size, presence of implant and its properties, infection, formation of fibrotic layer around the implant, other diseases of the patient, mechanical loading, etc. Stimulation of the formation of vascularized bone tissue using biomimetic materials and physical stimulation (electrical or mechanical) is important for improved bone tissue regeneration, osseointegration of bone prosthesis and its long-term function. Diamond layers are able to interact with various molecules and have been tested for their use in sensors. Further functionalization of the surface of the diamond layer will allow the establishment of specific interactions with both stem cells and endothelial cells, influencing cell adhesion, proliferation and differentiation, as well as creating an environment suitable for capillary formation.
The aim of the PhD thesis is to create an innovative biomimetic system, consisting of a three-dimensional porous scaffold covered with a functionalized diamond layer, that will stimulate human endothelial and mesenchymal stem cells and the formation of vascularized bone tissue in vitro by physical stimulation (electrical or mechanical) of the cells. In an interdisciplinary approach, in the biological part, it is possible to study cell adhesion, proliferation, and osteogenic differentiation of stem cells and the formation of capillary structures by endothelial cells. From the material point of view, it is possible to study the deposition and functionalization of diamond layers on porous scaffolds using plasma processes and subsequent characterization of the physical and chemical properties of the materials. Another possible aspect of the study is the influence of electrical or mechanical stimulation on stem cell and endothelial cell behavior and capillary formation.
Candidate’s profile (requirements):
A candidate should have a Master’s degree from a university in the natural sciences, biomedical engineering, or a related field, accept an interdisciplinary approach to the PhD program, and be able to communicate in English.
References:
Travnickova M, Vandrovcova M, Filova E, Steinerova M, Rackova J, Kocourek T, Bartova J, Suchy T, Zaloudkova M, Jelinek M, Bacakova L. Effect of diamond-like carbon doped with chromium on cell differentiation, immune activation and apoptosis. Eur Cell Mater. 2020 Nov 30;40:276-302. doi: 10.22203/eCM.v040a17. PMID: 33253412.
Steinerova M, Matejka R, Stepanovska J, Filova E, Stankova L, Rysova M, Martinova L, Dragounova H, Domonkos M, Artemenko A, Babchenko O, Otahal M, Bacakova L, Kromka A. Human osteoblast-like SAOS-2 cells on submicron-scale fibers coated with nanocrystalline diamond films. Mater Sci Eng C Mater Biol Appl. 2021 Feb;121:111792. doi: 10.1016/j.msec.2020.111792. Epub 2020 Dec 10. PMID: 33579442.
Travnickova M, Filova E, Slepicka P, Slepickova Kasalkova N, Kocourek T, Zaloudkova M, Suchy T, Bacakova L. Titanium-Doped Diamond-like Carbon Layers as a Promising Coating for Joint Replacements Supporting Osteogenic Differentiation of Mesenchymal Stem Cells. Int J Mol Sci. 2024 Feb 29;25(5):2837. doi: 10.3390/ijms25052837. PMID: 38474083; PMCID: PMC10932162.
The impact of biological sex on mitochondrial metabolism in cardiomyocytes
Laboratory name: Sex Chromosomes and Cardiometabolism
Supervisor (email): Lukáš Chmátal (chmatal@wi.mit.edu)
PhD Project: The impact of biological sex on mitochondrial metabolism in cardiomyocytes
Heart disease is the leading cause of death worldwide, with marked differences in symptoms, prevalence, and outcomes between sexes. Understanding the molecular mechanisms underlying these sex differences is key for addressing the unique needs of male and female patients. My lab has a deep interest in metabolic sex differences and their role in human health and disease. Our previous research showed that human heart metabolism differs between healthy males and females. Specifically, we showed that mitochondrial fatty acid oxidation – the main source of heart’s energy – is more potent in female cardiac cells compared to males. We thus ask a key biological question: How does biological sex influence overall mitochondrial metabolism and function in heart cells? Using state-of-the-art metabolomics, proteomics, and fluorescence microscopy in genetically engineered mouse models with fluorescently tagged cardiac mitochondria, we study how biological sex – a unique combination of sex chromosomes and sex hormones – shapes mitochondrial function. We’re looking for a passionate, curious, and collaborative individuals to join our emerging team. If you’re interested in mitochondrial biology, metabolism, and sex differences, we’d love to hear from you!
Candidate’s profile (requirements):
You hold a Master’s degree in biological, medical, chemical, or biochemical sciences, or you are on track to complete your studies this academic year. You are a motivated, detail-oriented individual with experience in cell biology, molecular biology, or metabolomics, and you are comfortable working with both mouse and human samples. You are fluent in English and have excellent communication skills and enjoy creating and working in an inclusive, supportive and collaborative team driven by a shared goal.
References:
Maya Talukdar*, Lukas Chmátal*, Linyong Mao, Daniel Reichart, Danielle Murashige, Yelena Skaletsky, Daniel M. DeLaughter, Zoltan Arany, Jonathan G. Seidman, Christine Seidman, David C. Page. Genes of fatty acid oxidation pathway are upregulated in the female as compared to male human cardiomyocytes. Circulation (2025), *co-first authors
Daniel Reichart, Gregory A. Newby, Hiroko Wakimoto, Mingyue Lun, Joshua M. Gorham, Justin J. Curran, Aditya, Raguram, Daniel M. DeLaughter, David A. Conner, Júlia D. C. Marsiglia1, Sajeev Kohli, Lukas Chmátal, David C. Page, Nerea Zabaleta, Luk Vandenberghe, David R. Liu, Jonathan G. Seidman, and Christine Seidman. Efficient in vivo genome editing prevents hypertrophic cardiomyopathy in mice. Nature Medicine, 29: 412-421 (2023)
Akera T., Chmátal L., Trimm E., Yang K., Aonbangkhen C., Chenoweth D.M., Janke C., Schultz R.M., Lampson M.A. Spindle asymmetry drives non-Mendelian chromosome segregation. Science, 358(6363): 668-672 (2017)
The impact of sex chromosomes on cardiometabolic adaptations during obesity
Laboratory name: Sex Chromosomes and Cardiometabolism
Supervisor (email): Lukáš Chmátal (chmatal@wi.mit.edu)
PhD Project: The impact of sex chromosomes on cardiometabolic adaptations during obesity
Heart disease is the leading cause of death worldwide, with significant differences in symptoms, prevalence, and outcomes between males and females. These sex differences are shaped by simultaneous contribution of various factors, including diet, exercise, sex hormones, and sex chromosomes. However, the specific impact of sex chromosomes, such as the “inactive” X chromosome (Xi) in females and the Y chromosome in males, on heart physiology and function remains poorly understood. To address this knowledge gap, we ask: How does the Xi regulate mitochondrial functions under normal and pathological conditions? To tackle this question, we have developed the MiCY* mouse model characterized by altered sex chromosome compositions, combined with established model with cardiomyocyte-specific fluorescently tagged outer mitochondrial membrane protein. This MiCY* mouse model allows us to isolate mitochondria specifically from cardiomyocytes, and study the effects of the Xi on mitochondrial physiology and function under both normal and obesity-related conditions. Using an integrated approach that combines heart physiology techniques, biochemistry, targeted and untargeted metabolomics, proteomics, and fluorescence microscopy, we will explore the role of the Xi chromosome and specific Xi-expressed genes in mitochondrial biology during both health and disease. This work will provide critical insights into how the Xi chromosome influences mitochondrial metabolism and contributes to cardiac health and disease.
Candidate’s profile (requirements):
You have completed, or are nearing the completion of, a Master’s degree in biological, medical, chemical, or biochemical sciences. You bring motivation, attention to detail, and hands-on experience in cell biology, molecular biology, or metabolomics. You are comfortable with handling mouse and human samples. You are fluent in English, have excellent communication skills and thrive in an inclusive, collaborative and supportive team that works towards a shared goal.
References:
Maya Talukdar*, Lukas Chmátal*, Linyong Mao, Daniel Reichart, Danielle Murashige, Yelena Skaletsky, Daniel M. DeLaughter, Zoltan Arany, Jonathan G. Seidman, Christine Seidman, David C. Page. Genes of fatty acid oxidation pathway are upregulated in the female as compared to male human cardiomyocytes. Circulation (2025), *co-first authors
Daniel Reichart, Gregory A. Newby, Hiroko Wakimoto, Mingyue Lun, Joshua M. Gorham, Justin J. Curran, Aditya, Raguram, Daniel M. DeLaughter, David A. Conner, Júlia D. C. Marsiglia1, Sajeev Kohli, Lukas Chmátal, David C. Page, Nerea Zabaleta, Luk Vandenberghe, David R. Liu, Jonathan G. Seidman, and Christine Seidman. Efficient in vivo genome editing prevents hypertrophic cardiomyopathy in mice. Nature Medicine, 29: 412-421 (2023)
Akera T., Chmátal L., Trimm E., Yang K., Aonbangkhen C., Chenoweth D.M., Janke C., Schultz R.M., Lampson M.A. Spindle asymmetry drives non-Mendelian chromosome segregation. Science, 358(6363): 668-672 (2017)
The role of hypoxia-inducible factor-1α on the progression of heart failure with preserved ejection fraction
Laboratory name: Experimental Hypertension
Supervisor (email): Jan Neckář, jan.neckar@fgu.cas.cz
PhD project: The role of hypoxia-inducible factor-1α on the progression of heart failure with preserved ejection fraction
Heart failure with preserved ejection fraction (HFpEF) is a complex, multi-organ disease affecting the heart, vasculature, and kidneys. Since the prevalence of HFpEF in the population has increased, developing new treatment approaches is at the forefront of current cardiovascular research. This project will explore the role of transcription factor hypoxia-inducible-1α (HIF-1α), a key regulator of adaptation to oxygen deprivation with protective potential for various cardiovascular diseases, in HFpEF progression. Using a novel and unique rat strain with partial HIF-1α deficiency (heterozygous SD-HIF+/-), we will investigate the progression of HFpEF, focusing on cardiovascular and renal function, as well as end-organ damage, under a high-fat diet and nitric oxide synthase inhibition (established HFpEF model) in the SD-HIF+/- and Sprague-Dawley (SD) controls. The project’s results may contribute to the development of novel therapeutic strategies for the treatment of HFpEF.
Candidate’s profile (requirements):
For this project, we seek students with a master’s degree in biomedical sciences (physiology, biochemistry and molecular biology, general medicine). We offer experimentally interesting and methodologically complex scientific work (echocardiography, telemetry, catheterization, electro-physiology, histology, modern molecular-biological methods, omics) on a topic at the front-line of current experimental and clinical cardiovascular research. Our laboratory has extensive experience in cardiovascular research and successfully supervises PhD students. A Czech Science Foundation grant supports the project.
References:
Hojná S, Malínská H, Hüttl M, Vaňourková Z, Marková I, Miklánková D, Hrdlička J, Papoušek F, Neckář J, Kujal P, Behuliak M, Rauchová H, Kadlecová M, Sedmera D, Neffeová K, Zábrodská E, Olejníčková V, Zicha J, Vaněčková I. Hepatoprotective and cardioprotective effects of empagliflozin in spontaneously hypertensive rats fed a high-fat diet. Biomed Pharmacother. 2024;174:116520.
Neckář J, Hsu A, Hye Khan MA, Gross GJ, Nithipatikom K, Cyprová M, Benák D, Hlaváčková M, Sotáková-Kašparová D, Falck JR, Sedmera D, Kolář F, Imig JD. Infarct size-limiting effect of epoxyeicosatrienoic acid analog EET-B is mediated by hypoxia-inducible factor-1α via downregulation of prolyl hydroxylase 3. Am J Physiol Heart Circ Physiol. 2018;315(5):H1148-H1158.
Cellular senescence-associated cardiovascular and renal diseases in hypertensive rats
Laboratory name: Experimental Hypertension
Supervisor (email): Jan Neckář, jan.neckar@fgu.cas.cz
PhD project: Cellular senescence-associated cardiovascular and renal diseases in hypertensive rats
Senescent cell accumulation is a fundamental aging process. In addition to aging, there is growing evidence that cellular senescence increases prevalence and contributes to the progression of many chronic diseases, including cardiovascular and renal (various forms of heart failure, coronary artery disease, hypertension, atherosclerosis, chronic kidney diseases, etc.). Eliminating senescent cells abrogated the senescence-associated secretory phenotype (mainly of proinflammatory cytokines and extracellular matrix modulators) and improved cardiac and renal functions. As a continuation of our ongoing research program, we will study the effect of cellular senescence on heart and renal function, vascular and autonomic regulation, and end-organ damage in a unique knockout strain of spontaneously hypertensive rats (SHR) with targeted Tert (Telomerase reverse transcriptase). Homozygous SHR-Tert-/- rats exhibit progressive telomere attrition in each generation, resulting in significant premature aging phenotype in the F3 generation. We will also study the role of intracellular signaling associated with Tert deficiency and the molecular and biological mechanisms of senescence. The impact of a partial deficiency of transcription factor hypoxia-inducible factor-1α (HIF-1α), a key regulator of adaptation to oxygen deprivation with protective potential for various cardiovascular diseases, will also be analyzed in aged (18 months) transgenic SHR strain (heterozygous SHR-HIF1a+/-). Finally, we plan to study the prevention of senescence progression by new senolytic drugs based on alkyl triphenylphosphonium salts in cooperation with the Institute for Clinical and Experimental Medicine (Dr. Štemberková Hubáčková group).
Candidate’s profile (requirements):
For this project, we seek students with a master’s degree in biomedical sciences (physiology, biochemistry and molecular biology, general medicine). We offer experimentally interesting and methodologically complex scientific work (echocardiography, telemetry, catheterization, electro-physiology, histology, modern molecular-biological methods, omics) on a topic at the front-line of current experimental and clinical cardiovascular research. Our laboratory has extensive experience in cardiovascular research and successfully supervises PhD students. A Czech Science Foundation grant supports the project.
References:
Vacurova E, Trnovska J, Svoboda P, Skop V, Novosadova V, Reguera DP, Petrezselyová S, Piavaux B, Endaya B, Spoutil F, Zudova D, Stursa J, Melcova M, Bielcikova Z, Werner L, Prochazka J, Sedlacek R, Huttl M, Hubackova SS, Haluzik M, Neuzil J. Mitochondrially targeted tamoxifen alleviates markers of obesity and type 2 diabetes mellitus in mice. Nat Commun. 2022;13(1):1866.
Neckář J, Hye Khan MA, Gross GJ, Cyprová M, Hrdlička J, Kvasilová A, Falck JR, Campbell WB, Sedláková L, Škutová Š, Olejníčková V, Gregorovičová M, Sedmera D, Kolář F, Imig JD. Epoxyeicosatrienoic acid analog EET-B attenuates post-myocardial infarction remodeling in spontaneously hypertensive rats. Clin Sci (Lond). 2019;133(8):939-951.
Mechanisms of protective effects of empagliflozin – the role of HIF-1α
Laboratory name: Experimental Hypertension
Supervisor (email): Ivana Vaněčková, ivana.vaneckova@fgu.cas.cz
PhD project: Mechanisms of protective effects of empagliflozin – the role of HIF-1α
Gliflozins, the inhibitors of sodium-glucose cotransporter type-2 (SGLT-2), are primarily antidiabetics, whose benefits have been demonstrated in many cardiovascular diseases. Although the principle mechanism of actions of SGLT-2 inhibitors is known – the blockade of the sodium-glucose co-transporter in the proximal tubule, leading to glycosuria and natriuresis – there are additional metabolic as well as anti-inflammatory and anti-oxidant effects beyond. In this context, the role of hypoxia-inducible factor-1α (HIF-1α) is newly discussed as the potential mechanism underlying gliflozin’s beneficial effects. Hypoxia-inducible factors belong to transcription factors that control the transcription rate of genes involved in angiogenesis, metabolism, erythropoiesis, and apoptosis, as well as inflammation and fibrosis, their effects being dependent on the oxygen level. Using two unique rat strains – HIF-1α knockouts – we will analyze whether HIF1α is the underlying factor responsible for the beneficial effects of empagliflozin under normoxic and hypoxic conditions. We shall investigate the effects of chronic empagliflozin treatment on cardiac, hepatic, metabolic, and renal parameters in normotensive and hypertensive rat strains fed a diet rich in fat, fructose, and cholesterol with a focus on the role of HIF-1α and hypoxia in its beneficial actions.
Candidate’s profile (requirements):
For this project, we seek students with a master’s degree in biomedical sciences (physiology, biochemistry and molecular biology, general medicine). We offer experimentally interesting and methodologically complex scientific work (from whole body to molecular biology methods) on a hot topic in contemporary biomedical experimental and clinical research. Our laboratory has extensive experience in cardiovascular research and successfully supervising PhD students.
References:
Hojná S, Malínská H, Hüttl M, Vaňourková Z, Marková I, Miklánková D, Hrdlička J, Papoušek F, Neckář J, Kujal P, Behuliak M, Rauchová H, Kadlecová M, Sedmera D, Neffeová K, Zábrodská E, Olejníčková V, Zicha J, Vaněčková I. Hepatoprotective and cardioprotective effects of empagliflozin in spontaneously hypertensive rats fed a high-fat diet. Biomed Pharmacother. 2024;174:116520.
Malínská H, Hüttl M, Marková I, Miklánková D, Hojná S, Papoušek F, Šilhavý J, Mlejnek P, Zicha J, Hrdlička J, Pravenec M, Vaněčková I. Beneficial effects of empagliflozin are mediated by reduced renal inflammation and oxidative stress in spontaneously hypertensive rats expressing human C-reactive protein. Biomedicines. 2022;10(9):2066.
Hojná S, Rauchová H, Malínská H, Marková I, Hüttl M, Papoušek F, Behuliak M, Miklánková D, Vaňourková Z, Neckář J, Kadlecová M, Kujal P, Zicha J, Vaněčková I. Antihypertensive and metabolic effects of empagliflozin in Ren-2 transgenic rats, an experimental non-diabetic model of hypertension. Biomed Pharmacother. 2021;144:112246.
