Transcription regulation in embryonal development and the pathogenesis of disease
Laboratory of Molecular Pathogenetics
Group leader: RNDr. Gabriela Pavlínková, Ph.D.
Our research program is focused on transcriptional regulation during embryonic development, the molecular mechanisms of developmental programming, and identification of the molecular causes of abnormal embryonic development and disease predispositions. We are particularly interested in HIF-1, ISL1, SOX2, and NEUROD1 transcription factor networks and how their dysfunction affects embryonic development and can increase pre-dispositions of an individual to diseases such as diabetes, heart disease or hearing loss. We are also analyzing the combinatorial effects of the environment (e.g. diabetes) and genetic mutations. Using mouse models, and single cell and bulk transcriptome analyses, we are studying molecular mechanisms to identify targets for the development of preventive and diagnostic strategies.
About 422 million people worldwide have diabetes. Diabetes is a metabolic disease that involves the death or dysfunction of the insulin-secreting beta cells in the pancreas. Understanding how developmental and environmental cues shape cellular identity and contribute to the manifestation of pancreatic diseases, could have valuable implications for treatment strategies.
Diabetes is associated with a majority of risk health factors, such as hypertension, heart disease, obesity, autonomic neuropathy, nephropathy, and microvascular pathology. Hypoxia is another important pathophysiological factor associated with diabetic complications. Transcriptional responses to hypoxia are mediated by hypoxia inducible factor 1 (HIF-1). The aim of our research is to examine HIF-1 function in diabetes and heart disease.
Diabetes of the mother represents a serious complication for the developing embryo with an increased incidence of congenital malformations. Even without congenital abnormalities, the risk for diabetes and cardiovascular disease is elevated in offspring exposed to adverse intrauterine conditions. This phenomenon is also termed fetal or developmental programming. The overarching goal of our research is to identify the key molecular players in changes caused by the exposure to diabetes.
Approximately 71 million Europeans have a hearing impairment. Ageing societies face a global pandemic of around 900 million hearing impaired people by 2050. Neurosensory hearing loss is permanent and results from the death of neurons or sensory cells, which have little ability to regenerate. Although cochlear implants can restore some hearing, regenerating lost neurosensory cells and to delay or even prevent the onset of hearing loss are the most important targets for the immediate future. Our overreaching goal is to understand the molecular interactions necessary for neurosensory development and maintenance and to use this knowledge as a basis for new therapeutic strategies.
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Bohuslavova R, Smolik O, Malfatti J, Berkova Z, Novakova Z, Saudek F, Pavlinkova G (2021) "NEUROD1 Is Required for the Early α and β Endocrine Differentiation in the Pancreas." Int Journal of Mol Sci 22, 6713. https://doi.org/10.3390/ijms22136713
Elliott KL, Kersigo JM, Lee JH, Jahan I, Pavlinkova G, Fritzsch B, Yamoah EN (2021) "Changes in Peripherin-eGFP expression in spiral ganglion neurons; from development to maturity." Front in Cell Neuroscience. https://doi.org/10.3389/fncel.2021.678113
Elliott KL, Pavlinkova G, Chizhikov VV, Yamoah EN, Fritzsch B. (2021) "Neurog1, Neurod1, and Atoh1 are essential for spiral ganglia, cochlear nuclei, and cochlear hair cell development."F1000 Faculty Reviews 10:(47)
Elliott KL, Pavlínková G, Chizhikov VV, Yamoah EN, Fritzsch B (2021) "Development in the Mammalian Auditory System Depends on Transcription Factors." Int Journal of Mol Sci , 22(8), 4189; https://doi.org/10.3390/ijms22084189
Chumak T, Tothova D, Filova I, Bures Z, Popelar J, Pavlinkova G, Syka J (2021) "Overexpression of Isl1 under the Pax2 Promoter, Leads to Impaired Sound Processing and Increased Inhibition in the Inferior Colliculus" Int Journal of Mol Sci 26;22(9):4507, https://doi.org/10.3390/ijms22094507.
- Pavlinkova G. (2021) "Molecular Aspects of the Development and Function of Auditory Neurons" Int Journal of Mol Sci 22(1), 131, https://doi.org/10.3390/ijms22010131
Dvorakova, M., I. Macova, R. Bohuslavova, M. Anderova, B. Fritzsch and G. Pavlinkova (2020). "Early ear neuronal development, but not olfactory or lens development, can proceed without SOX2." Dev Biol 457(1): 43-56.
- Filova I, Dvorakova M, Bohuslavova R, Pavlinek A, Elliott KL, Vochyanova S, Fritzsch B, Pavlinkova G."Combined Atoh1 and Neurod1 Deletion Reveals Autonomous Growth of Auditory Nerve Fibers."Molecular Neurobiology (2020) 57: 5307–5323
- Hylmarova, S., Stechova, K., Pavlinkova, G., Peknicova, J., Macek, M., Kvapil, M. "The impact of type 1 diabetes mellitus on male sexual functions and sex hormone levels." Endocrine Journal (2020), 67(1):59-71. doi: 10.1507/endocrj.EJ19-0280. ISSN: 1348-4540.
- Pavlinkova G. "Molecular Aspects of the Development and Function of Auditory Neurons." Int. J.MolSci. 2020, 22(1), 131
Bohuslavova, R., R. Cerychova, F. Papousek, V. Olejnickova, M. Bartos, A. Gorlach, F. Kolar, D. Sedmera, G. L. Semenza and G. Pavlinkova (2019). "HIF-1alpha is required for development of the sympathetic nervous system." Proc Natl Acad Sci U S A 116(27): 13414-13423.
Fritzsch, B., K. L. Elliott and G. Pavlinkova (2019). "Primary sensory map formations reflect unique needs and molecular cues specific to each sensory system." F1000Res 8.
Fritzsch, B., K. L. Elliott, G. Pavlinkova, J. S. Duncan, M. R. Hansen and J. M. Kersigo (2019). "Neuronal Migration Generates New Populations of Neurons That Develop Unique Connections, Physiological Properties and Pathologies." Front Cell Dev Biol 7: 59.
Macova, I., K. Pysanenko, T. Chumak, M. Dvorakova, R. Bohuslavova, J. Syka, B. Fritzsch and G. Pavlinkova (2019). "Neurod1 Is Essential for the Primary Tonotopic Organization and Related Auditory Information Processing in the Midbrain." J Neurosci 39(6): 984-1004.
Cerychova, R., R. Bohuslavova, F. Papousek, D. Sedmera, P. Abaffy, V. Benes, F. Kolar and G. Pavlinkova (2018). "Adverse effects of Hif1a mutation and maternal diabetes on the offspring heart." Cardiovasc Diabetol 17(1): 68.
Cerychova, R. and G. Pavlinkova (2018). "HIF-1, Metabolism, and Diabetes in the Embryonic and Adult Heart." Front Endocrinol (Lausanne) 9: 460.
Kersigo, J., N. Pan, J. D. Lederman, S. Chatterjee, T. Abel, G. Pavlinkova, I. Silos-Santiago and B. Fritzsch (2018). "A RNAscope whole mount approach that can be combined with immunofluorescence to quantify differential distribution of mRNA." Cell Tissue Res 374(2): 251-262.
Bohuslavova, R., R. Cerychova, K. Nepomucka and G. Pavlinkova (2017). "Renal injury is accelerated by global hypoxia-inducible factor 1 alpha deficiency in a mouse model of STZ-induced diabetes." BMC Endocr Disord 17(1): 48.
Bohuslavova, R., N. Dodd, I. Macova, T. Chumak, M. Horak, J. Syka, B. Fritzsch and G. Pavlinkova (2017). "Pax2-Islet1 Transgenic Mice Are Hyperactive and Have Altered Cerebellar Foliation." Mol Neurobiol 54(2): 1352-1368.
Pavlinkova, G., H. Margaryan, E. Zatecka, E. Valaskova, F. Elzeinova, A. Kubatova, R. Bohuslavova and J. Peknicova (2017). "Transgenerational inheritance of susceptibility to diabetes-induced male subfertility." Sci Rep 7(1): 4940.
Dvorakova, M., I. Jahan, I. Macova, T. Chumak, R. Bohuslavova, J. Syka, B. Fritzsch and G. Pavlinkova (2016). "Incomplete and delayed Sox2 deletion defines residual ear neurosensory development and maintenance." Sci Rep 6: 38253.
Chumak, T., R. Bohuslavova, I. Macova, N. Dodd, D. Buckiova, B. Fritzsch, J. Syka and G. Pavlinkova (2016). "Deterioration of the Medial Olivocochlear Efferent System Accelerates Age-Related Hearing Loss in Pax2-Isl1 Transgenic Mice." Mol Neurobiol 53(4): 2368-2383.
Bohuslavova, R., L. Skvorova, R. Cerychova and G. Pavlinkova (2015). "Gene expression profiling of changes induced by maternal diabetes in the embryonic heart." Reprod Toxicol 57: 147-156.
Ornoy, A., E. A. Reece, G. Pavlinkova, C. Kappen and R. K. Miller (2015). "Effect of maternal diabetes on the embryo, fetus, and children: congenital anomalies, genetic and epigenetic changes and developmental outcomes." Birth Defects Res C Embryo Today 105(1): 53-72.
Bohuslavova, R., F. Kolar, D. Sedmera, L. Skvorova, F. Papousek, J. Neckar and G. Pavlinkova (2014). "Partial deficiency of HIF-1alpha stimulates pathological cardiac changes in streptozotocin-induced diabetic mice." BMC Endocr Disord 14: 11.
Bohuslavova, R., L. Skvorova, D. Sedmera, G. L. Semenza and G. Pavlinkova (2013). "Increased susceptibility of HIF-1alpha heterozygous-null mice to cardiovascular malformations associated with maternal diabetes." J Mol Cell Cardiol 60: 129-141.
Salbaum, J. M., C. Kruger, X. Zhang, N. A. Delahaye, G. Pavlinkova, D. H. Burk and C. Kappen (2011). "Altered gene expression and spongiotrophoblast differentiation in placenta from a mouse model of diabetes in pregnancy." Diabetologia 54(7): 1909-1920.
Bohuslavova, R., F. Kolar, L. Kuthanova, J. Neckar, A. Tichopad and G. Pavlinkova (2010). "Gene expression profiling of sex differences in HIF1-dependent adaptive cardiac responses to chronic hypoxia." J Appl Physiol (1985) 109(4): 1195-1202.
GAČR: GA21-03847S, G. Pavlínková: Role of HIF-1α in the development of the cardiac sympathetic nervous system. 2021-2023.
AZV: NU20J-02-00035, G. Pavlínková: Ischemická tolerance srdcí adaptovaných na chronickou hypoxii: úloha hypoxií-indukovaného faktoru 1alfa a mitochondrií. 2020-2023.
GAUK: 176120, O. Smolík: Role transkripčního faktoru Islet-1 v diferenciaci endokrinních prekurzorů pankreatu.
GAČR: GA20-06927S, G. Pavlínková: The role of NEUROD1 and ISL1 in neuronal development of the inner ear. 2020-2022.
GAČR: GA19-07378S, G. Pavlínková: Interplay between ISLET1 and NEUROD1 in pancreatic development and disease. 2019-2021.
GAČR: GA17-04719S, G. Pavlínková: Influence of the transcriptional regulation on the neurosensory development and function of the auditory system. 2017-2019.
GAČR: GA16-06825S, G. Pavlínková: Programming of the developing heart by maternal diabetes. 2016-2018.
GAUK: 780216 Functional role of Sox2 in neurosensoric development of inner ear. 2016.
GAUK: 228416 Role of HIF-1 signalization in diabetic embryopathy. 2016.
GAČR: GA16-06825S, G. Pavlínková: Programming of the developing heart by maternal diabetes. 2016-2018.
GAUK: 324615 Transcription regulation during the development of inner ear. 2015.
GAČR: GA13-07996S, G. Pavlínková: Molecular mechanisms in specification and differentiation of neurosensory cells in the inner ear development. 2013-2016.
MŠMT: CZ.1.07/2.3.00/30.0020, Schneider, Charnavets, Pavlínková, Dodd, Hejnalová: Biotechnological expert. 2012-2015.
GAČR: GA301/09/0117, G. Pavlínková: Molecular Mechanisms in Diabetic Embryopathy. 2009-2013.
FP7 IRG Reintegration Grant: 224760, G. Pavlínková: Molecular Mechanisms in Diabetic Embryopathy. 2008-2012.