IPHYS
Open position for PhD student at IPHYS for the academic year 2022-2023.
Laboratory: Membrane Transport
Project supervisor : Olga Zimmermannová, Ph.D. (olga.zimmermannova@fgu.cas.cz)
Laboratory website: https://www.fgu.cas.cz/en/departments/laboratory-of-membrane-transport
PhD project:
Project title: Identification of new regulatory mechanisms important for the maintenance of monovalent cation homeostasis in eukaryotic cells
Project summary:
The tight regulation of intracellular ion concentrations is crucial for all living cells. All types of cells employ various types of cation importers and exporters to ensure the optimal high levels of indispensable potassium, low levels of toxic sodium cations, and stable intracellular pH. Disordered performance of ion transporters and, consequently, non-optimal ion homeostasis result in many pathological processes. Cation/H+ exchangers (CPA/SLC9 family) belong among cation-transport systems that help to ensure the optimal intracellular levels of alkali-metal cations and protons (pH) in cells of most organisms (from bacteria to humans). The PhD project will study cation/H+ exchangers from eukaryotic cells (yeasts and mammals) with the aims of (i) determining new structural and functional elements in these proteins, (ii) unravelling new mechanisms of their regulation, and (iii) identifying so far unknown proteins that participate in their biogenesis and degradation. Obtained results will help to uncover cation-transport mechanism across membranes at the molecular level and will provide new insights into the cell cation-homeostasis regulatory network both in lower and higher eukaryotes.
Candidate’s profile (requirements):
The candidate should be highly self-motivated with master’s degree or equivalent (obtained before October 2022) in molecular biology, biochemistry, microbiology or related fields. Fluent English, as well as some experience in basic laboratory (PCR, DNA and protein electrophoresis, bacteria transformation, plasmid isolation) and basic bioinformatics (DNA and protein sequence search and comparison, sequenced fragments analysis, plasmid and primers design) techniques are necessary.
References:
Papouskova K et al. C5 conserved region of hydrophilic C-terminal part of Saccharomyces cerevisiae Nha1 antiporter determines its requirement of Erv14 COPII cargo receptor for plasma-membrane targeting. Mol Microbiol 115(1):41-57 (2021); doi: 10.1111/mmi.14595.
Albacar M et al. The Toxic effects of Ppz1 overexpression involve Nha1-mediated deregulation of K+ and H+ homeostasis. J. Fungi 7(12):1010 (2021); doi: 10.3390/jof7121010.
Smidova A et al. The activity of Saccharomyces cerevisiae Na+, K+/H+ antiporter Nha1 is negatively regulated by 14-3-3 protein binding at serine 481. BBA – Mol. Cell Res. 1866: 118534 (2019).
Zimmermannova O. et al. Erv14 cargo receptor participates in regulation of plasma-membrane potential, intracellular pH and potassium homeostasis via its interaction with K+-specific transporters Trk1 and Tok1. BBA – Mol. Cell Res. 1866: 1376–1388 (2019).
Laboratory: Translational Metabolism
Project supervisor : Assoc. Prof. Tomas Cajka, Ph.D. (tomas.cajka@fgu.cas.cz)
Laboratory website: https://www.fgu.cas.cz/en/departments/laboratory-of-translational-metabolism
PhD project:
Project title: Liquid chromatography-mass spectrometry for comprehensive characterization of the metabolome and lipidome of biological samples
Project summary:
Over the last decade, mass spectrometry-based metabolomics and lipidomics have become established as the key platforms for comprehensive profiling of polar metabolites and complex lipids in biological samples (plasma, serum, urine, tissues). Coupling liquid chromatography to mass spectrometry (LC-MS) is the preferred technique in metabolomics and lipidomics permitting effective compound separations and detection. However, there is still a lack of sufficient data on the metabolome and lipidome characterizing biofluids and tissues which can be easily accessible and reused at any time for future studies. The Ph.D. project aims to focus on novel approaches for comprehensive characterization of the metabolome and lipidome in biological samples, specifically, (i) merging targeted and untargeted methods, (ii) increasing the coverage of spectral libraries used for metabolite annotation, and (iii) using bioinformatics tools for visualization and interpretation of the data obtained within metabolomics and lipidomics studies. The work will be conducted at the Institute of Physiology CAS and financially supported by various grants (GACR, MSMT, AZV).
Candidate’s profile (requirements):
We are seeking outstanding self-motivated candidates with master’s degree or equivalent in analytical chemistry, biochemistry, or related fields, or those expecting to obtain their degree this year. Candidates should be fluent in English. Experience with LC-MS as well as processing of metabolomics and lipidomics data sets are advantage.
References:
- H. Tsugawa, K. Ikeda, M. Takahashi, A. Satoh, Y. Mori, H. Uchino, N. Okahashi, Y. Yamada, I. Tada, P. Bonini, Y. Higashi, Y. Okazaki, Z. Zhou, Z.-J. Zhu, J. Koelmel, T. Cajka, O. Fiehn, K. Saito, M. Arita, M. Arita: A lipidome atlas in MS-DIAL 4. Nature Biotechnology 38 (2020) 1159–1163.
- I. Nemet, P.P. Saha, N. Gupta, W. Zhu, K.A. Romano, S.M. Skye, T. Cajka, M.L. Mohan, L. Li, Y. Wu, M. Funabashi, A.E. Ramer-Tait, S.V.N. Prasad, O. Fiehn, F.E. Rey, W.H.W. Tang, M.A. Fischbach, J.A. DiDonato, S.L. Hazen: A Cardiovascular disease-linked gut microbial metabolite acts via adrenergic receptors. Cell 180 (2020) 862–877.
- T. Cajka, J.T. Smilowitz, O. Fiehn: Validating quantitative untargeted lipidomics across nine liquid chromatography–high-resolution mass spectrometry platforms. Analytical Chemistry 89 (2017) 12360–12368.
Laboratory: Experimental Hypertension
Project supervisor : RNDr. Ivana Vaněčková, DSc. (Ivana.Vaneckova@fgu.cas.cz)
Laboratory website: https://www.fgu.cas.cz/en/departments/experimentalni-hypertenze
PhD project:
Project title: Gliflozins in the treatment of non-diabetic models of chronic kidney disease and heart failure
Project summary:
The new class of antidiabetic drugs, gliflozins (inhibitors of sodium-glucose transporter 2 – SGLT-2), exert their hypoglycaemic effects through the inhibition of the sodium-glucose transporter at renal proximal tubule promoting glucose and sodium excretion. This leads not only to a significant improvement in the control of blood glucose but also promotes the lowering of blood pressure and body weight both in diabetic patients and in experimental diabetic models. There is numerous experimental data on the effects of different gliflozins (empagliflozin, dapagliflozin, canagliflozin) in diabetic kidney and heart disease. However, the experiments in non-diabetic animals are relatively scarce. Therefore, the aim of the PhD project will be the study mechanisms of actions of these new class of antidiabetic drugs under non-diabetic conditions.
Candidate’s profile (requirements):
We are looking for motivated candidates with master’s degree in physiology, medicine or related fields. They should be fluent in English and interested in the work with experimental animals.
References:
Hüttl et al, Metabolic cardio- and reno-protective effects of empagliflozin in a prediabetic rat model, J Physiol Pharmacol, 71(5), 2020
Hojná et al: Antihypertensive and metabolic effects of empagliflozin in Ren-2 transgenic rats, a non-diabetic model of hypertension, Biomed Pharmacother. 2021;144:112246.
Trnovska J et al: Complex Positive Effects of SGLT-2 Inhibitor Empagliflozin in the Liver, Kidney and Adipose Tissue of Hereditary Hypertriglyceridemic Rats: Possible Contribution of Attenuation of Cell Senescence and Oxidative Stress. Int J Mol Sci. 2021;22(19):10606
Laboratory: Molecular neurobiology
Project supervisor : Martin Balastik, Ph.D. (martin.balastik@fgu.cas.cz)
Laboratory website: https://www.fgu.cas.cz/en/departments/molekularni-neurobiologie
PhD project:
Project title: Molecular mechanisms in cortical development and its malformations – the role of microtubule associated proteins.
Project summary:
Development of the cerebral cortex requires a highly-coordinated interplay of multiple processes including neuron migration, polarization, guidance, synapse formation and refinement. A key factor underlying the above-mentioned processes is a precisely regulated remodelling of the neuronal cytoskeleton, which is dominated by changes of actin and microtubule activity. Microtubules seem to play a particularly important role in cortical development since multiple gene mutations in tubulin or microtubule-associated proteins (MAPs) have been associated with malformations of cortical development (MCD). Unfortunately, the effect of most of the MCD-associated MAP mutations on microtubule dynamics or neural development are still largely unknown.
We have recently shown that microtubule-associated protein CRMP2 (Collapsin response mediator protein 2) controls synaptic pruning in early postnatal stages and that its deficiency shares histological and behavioral features of autism spectrum disorder.
The aim of this PhD project is to functionally characterize new MAP gene variants identified by deep gene sequencing of patients with MCD. Using biochemical and molecular biology techniques the PhD student will generate new cellular (primary neuron) and organismal (mouse) models and analyze the function of the new MAP variants by molecular, histological, and state of the art microscopy techniques. The project will uncover new molecular mechanisms in cortical development and in the pathogenesis of neurodevelopmental disorders.
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, Ankol L, Gradus Pery T, Altman T, Ionescu A, Weissova R, Ostrovsky M, Tank E, Alexandra G, Shelestovich N, Opatowsky Y, Dori A, Barmada S, Balastik M, Perlson E. A CRMP4-dependent retrograde axon-to-soma death signal in amyotrophic lateral sclerosis. EMBO J. 2021 Jun 30:e107586.
- Ziak J, et al, CRMP2 mediates Sema3F-dependent axon pruning and dendritic spine remodeling, EMBO Rep, 2020 Mar 4;21(3):e48512.
• Balastik M, et al., Prolyl Isomerase Pin1 Regulates Axon Guidance by Stabilizing CRMP2A Selectively in Distal Axons. Cell Rep. 2015 Oct 27;13(4):812-28.
Laboratory: Laboratory of Pain Research
Project supervisor : Jiri Palecek, M.D., Ph.D.,
Laboratory website: https://www.fgu.cas.cz/departments/vyzkum-bolesti
PhD project:
Project title: Modulation of nociceptive signaling at spinal cord level.
Project summary:
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 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 allodynia, hyperalgesia, neuropathic and cancer related pain. This project will be focused on modulation of synaptic transmission at the spinal cord level. Lately we are interested in the role of TRPV1 receptors, cannabinoids, opioids and inflammatory cytokines in this process. In our research we use mainly electrophysiological, imaging, immunohistochemical and behavioral methods.
Candidate’s profile (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, cell biology, molecular biology or electrophysiology techniques would be an advantage. Candidates should be fluent in Czech or English.
Selected relevant Publications:
2 Activation Contributes to Hypersensitivity Induced by Peripheral Inflammation in Rats. IJMS. 2021; 22(3)); 991 . IF = 5.9, Q1
M. Heles, P. Mrozkova, D. Sulcova, P. Adamek, D. Spicarova and J. Palecek, Chemokine CCL2 prevents opioid induced inhibition of nociceptive synaptic transmission in spinal cord dorsal horn. Journal of Neuroinflammation (2021) 18:279, IF=8.23, Q1
P Adamek, M Heles, A Bhattacharyya, M Pontearso, J Slepicka and J Palecek. Dual PI3Kδ/γ Inhibitor Duvelisib Prevents Development of Neuropathic Pain in Model of Paclitaxel-Induced Peripheral Neuropathy. Journal of Neuroscience IF = 6.2, Q1 (2022)
Laboratory: Bioenergetics
Project supervisor: RNDr. Tomáš Mráček, Ph.D. (tomas.mracek@fgu.cas.cz)
Laboratory website: http://www.fgu.cas.cz/en/departments/bioenergetics
PhD project:
Project title: Molecular mechanisms of pathogenicity in ATP synthase disorders
Project summary:
Mutations in mitochondrial FoF1 ATP synthase responsible for severe inborn errors of metabolism. As is the case with other mitochondrial diseases, one of the striking features is the tissue specificity of symptoms associated with mutations in individual subunits. Thus, mutations in TMEM70 or ATP5E present primarily as myopathies, while Usmg5 patients present with neurological disorders. While the primary biochemical features are generally characterised, mechanisms dictating tissue specificity are still poorly understood.
Recently, we have developed animal models for defects in TMEM70 as well as Usmg5. The aim of this project is to explore differences in tissue presentation as well as compensatory or regulatory mechanisms involved to mitigate pathogenic phenotype. The project should aim beyond the biochemical characterisation of mitochondrial function and dig further into the adaptations occurring at the whole-body level to understand the role of ATP synthase in modulation of metabolic plasticity. This project should take the advantage of wide array of phenotypisation techniques available at the Institute of Physiology and adapt them for the use on mitochondrial models.
Candidate’s profile (requirements):
We are seeking for highly motivated person with MSc. or equivalent degree in cell biology, biochemistry, physiology, or similar field obtained in 2019 or later. Candidate should be fluent in English and apart from the experimental “wet” work, she/he should be willing to work with laboratory animals.
References:
1. Kovalčíková J, Vrbacký M, Pecina P, Tauchmannová K, Nůsková H, Kaplanová V, Brázdová A, Alán L, Eliáš J, Čunátová K, Kořínek V, Sedlacek R, Mráček T, Houštěk J.: TMEM70 facilitates biogenesis of mammalian ATP synthase by promoting subunit c incorporation into the rotor structure of the enzyme. FASEB J. 2019 Dec;33(12):14103-14117
2. Vrbacky M, Kovalcikova J, Chawengsaksophak K, Beck IM, Mracek T, Nuskova H, Sedmera D, Papousek F, Kolar F, Sobol M, Hozak P, Sedlacek R, Houstek J. Knockout of Tmem70 alters biogenesis of ATP synthase and leads to embryonal lethality in mice. Hum Mol Genet. 2016;25(21):4674-85.
Laboratory: Bioenergetics
Project supervisor: Mgr. Petr Pecina, Ph.D. (petr.pecina@fgu.cas.cz)
Laboratory website: http://www.fgu.cas.cz/en/departments/bioenergetics
PhD project:
Project title: Regulation of mitochondrial oxidative phosphorylation by tissue-specific isoforms of cytochrome c oxidase
Project summary:
Mitochondrial cytochrome c oxidase (COX) is a key enzyme of oxidative phosphorylation (OXPHOS) system responsible for ATP production in mammalian cells. Expression of tissue-specific isoforms of COX subunits represents a crucial mechanism of OXPHOS regulation. Recently, our studies helped establish the lung isoform of regulatory subunit 4 (COX4I2) as a key component of functionally modified COX with reduced oxygen affinity dedicated to oxygen sensing. Our focus is now expanded to subunit COX6B that occurs either as ubiquitous isoform (COX6B1) or as a protein with exclusive testicular expression (COX6B2). Also, ectopic COX6B2 expression was associated with poor prognosis of lung carcinoma (LC). The project aims to explore the understudied phenomenon of COX6B isoform exchange and its effect on structure and function of OXPHOS. COX6B knock-out/knock-in models will be constructed in HEK293 and LC cell lines to characterize basic functional features of subunit isoforms and their impact on proliferation and tumorigenesis of LC. The role COX6B2 and its post-translational modification will also be studied in the physiological context of sperm maturation and capacitation. The proposed research will provide novel data on OXPHOS biogenesis and regulation and the role of these processes in carcinogenesis and male fertility.
Candidate’s profile (requirements):
We are seeking for highly motivated person with MSc. or equivalent degree in cell biology, biochemistry, physiology, or similar field obtained in 2019 or later. Candidate should be fluent in English.
References:
1. Pajuelo Reguera, D., K. Cunatova, M. Vrbacky, A. Pecinova, J. Houstek, T. Mracek and P. Pecina (2020). “Cytochrome c Oxidase Subunit 4 Isoform Exchange Results in Modulation of Oxygen Affinity.” Cells 9(2).
2. Čunátová, K., D. Pajuelo Reguera, M. Vrbacký, E. Fernández-Vizarra, S. Ding, I. Fearnley, M. Zeviani, J. Houštěk, T. Mráček and P. Pecina (2021). “Loss of COX4i1 leads to combined respiratory chain deficiency and impaired mitochondrial proteosynthesis.” Cells 10(2).
Laboratory: Molecular Physiology of Bone; Institute of Physiology of the Czech Academy of Sciences, Prague, Czech Republic
Project supervisor: Michaela Tencerova, Ph.D. (Michaela.Tencerova@fgu.cas.cz)
Laboratory website: http://www.fgu.cas.cz/en/departments/bioenergetics
PhD project:
Project title: Studying bone and fat metabolism in mice with different susceptibility to obesity
Project summary:
Obesity-associated diseases, including bone fractures are not manifested in all obese subjects. They are classified as metabolically healthy obese and may represent a model for better understanding the link between obesity and metabolic bone diseases. However, the molecular mechanism behind this phenomenon is not well documented. The aim of this proposal using two mouse strains with different propensity to obesity, B6 and A/J mice, is to investigate whether different response to obesogenic condition activates different metabolic pathways important for stem cell differentiation and nutrient utilization in bone marrow mesenchymal stem cells(BM-MSCs) in relation to bone and adipose metabolism. The project will employ murine and human cellular systems and in vivo models applying several molecular, bioanalytical and in vivo phenotyping techniques. Project will be conducted at the Institute of Physiology CAS in collaboration with excellent laboratories
abroad. The basic PhD scholarship will be supported by Czech Science Foundation.
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.
Relevant publications:
-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
- doi: 10.1002/jbmr.3408.
- Tencerova M, Kassem M. The Bone Marrow-Derived Stromal Cells: Commitment and
Regulation of Adipogenesis. Front Endocrinol (Lausanne). 2016 Sep 21;7:127.
Laboratory: Adipose Tissue Biology
Project supervisor: Martin Rossmeisl, MD, Ph.D. (martin.rossmeisl@fgu.cas.cz)
Laboratory website: https://www.fgu.cas.cz/en/departments/laboratory-of-adipose-tissue-biology
PhD project:
Project title: The role of impaired autophagy in NAFLD development and its restoration to improve the efficacy of n-3 fatty acids
Project summary:
Obesity is associated with non-alcoholic fatty liver disease (NAFLD), which represents a spectrum of conditions ranging from increased intrahepatic accumulation of triacylglycerols (hepatic steatosis) to non-alcoholic steatohepatitis (NASH) characterized by hepatocellular inflammation that can progress to fibrosis, cirrhosis and hepatocellular carcinoma. The mechanisms involved in the transition from benign steatosis to the more clinically severe stages of NAFLD are not fully understood. The severity of NAFLD may be related to autophagy failure leading to accumulation of dysfunctional peroxisomes associated with induction of oxidative tissue damage. Dietary n-3 fatty acid (omega-3) supplementation may modulate lipid metabolism, thereby reducing hepatic steatosis, but its efficacy on more advanced stages of NAFLD (e.g. NASH) is low.
The aim of this PhD project is to characterize the role of impaired autophagy in NAFLD progression, the effects of omega-3 supplementation on different stages of NAFLD, and the potential benefits of combined treatment with autophagy inducers and omega-3. The selected PhD student will conduct dietary intervention studies using several chemical forms of omega-3 in a mouse model of advanced obesity-related NAFLD. This will include phenotyping of glucose metabolism and insulin resistance in vivo (tolerance assays, hyperinsulinemic-euglycemic clamp), ex vivo functional analyses in isolated hepatocytes, as well as biochemical, histological, and molecular biological techniques.
Candidate’s profile (requirements):
We are seeking outstanding self-motivated candidates with master’s degree or equivalent in physiology, biochemistry, molecular biology, medicine or related fields, or those expecting to obtain their degree this year. Candidates should be fluent in English. This position involves extensive work with laboratory animals (primarily mice). Experience with animal models (mouse, rat), in vivo phenotyping techniques, in vitro cell cultures and/or molecular biology techniques is advantage.
Relevant publications:
- Mitrovic M. et al., Omega-3 phospholipids and obesity-associated NAFLD: Potential mechanisms and therapeutic perspectives. Eur J Clin Invest. 2021 Jul 22;e13650.
- Sistilli G. et al., Krill Oil Supplementation Reduces Exacerbated Hepatic Steatosis Induced by Thermoneutral Housing in Mice with Diet-Induced Obesity. Nutrients. 2021 Jan 29;13(2):437.
- Rossmeisl M. et al., Increased plasma levels of palmitoleic acid may contribute to beneficial effects of Krill oil on glucose homeostasis in dietary obese mice. Biochim Biophys Acta Mol Cell Biol Lipids. 2020 Aug;1865(8):158732.