Laboratory of Molecular Pathogenetics

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.

Follow us on Twitter: @PavlinkovaLab

2024

• Kolesova H, Hrabalova P, Bohuslavova R, Abaffy P, Fabriciova V, Sedmera D, and Pavlinkova G*. Reprogramming of the developing heart by Hif1a-deficient sympathetic system and maternal diabetes exposure. Frontiers in Endocrinology 2024 March 5, 15 https://doi.org/10.3389/fendo.2024.1344074

• Pyott SJ, Pavlinkova G, Yamoah NE, Fritzsch B. Harmony in the Molecular Orchestra of Hearing: Developmental Mechanisms from the Ear to the Brain. Annual Review of Neuroscience. 2024 Feb 15. Vol 47; https://doi.org/10.1146/annurev-neuro-081423-093942

2023

• Bohuslavova R, Fabriciova V, Lebrón-Mora L, Malfatti J, Smolik O, Valihrach L, Benesova S, Zucha D, Berkova Z, Saudek F, Evans SM, Pavlinkova G. (2023) "ISL1 controls pancreatic alpha cell fate and beta cell maturation." Cell Biosci. 10;13(1):53. https://doi:10.1186/s13578-023-01003-9

• Bohuslavova, R., Fabriciova, V., Smolik, O., Lebron-Mora, L., Abaffy, P., Benesova, S., Zucha, D., Valihrach, L., Berkova, Z., Saudek, F., Pavlinkova, G.(2023)"NEUROD1 reinforces endocrine cell fate acquisition in pancreatic development." Nat Commun 14, 5554. https://doi.org/10.1038/s41467-023-41306-6

• Hrabalova, P., Bohuslavova, R., Matejkova, K., Papousek, F., Sedmera, D., Abaffy, P., Kolar, F., Pavlinkova, G. (2023) "Dysregulation of hypoxia-inducible factor 1α in the sympathetic nervous system accelerates diabetic cardiomyopathy." Cardiovasc Diabetol 22, 88. https://doi.org/10.1186/s12933-023-01824-5

• Yamoah, E.N., Pavlinkova, G., Fritzsch, B.(2023) "The development of speaking and singing in infants may play a role in genomics and dementia in humans" Brain Sciences 13(8), 1190; https://doi.org/10.3390/brainsci13081190

2022

• Filova I, Pysanenko K, Tavakoli M, Vochyanova S, Dvorakova M, Bohuslavova R, Smolik O, Fabriciova V, Hrabalova P, Benesova S, Valihrach L, Cerny J, Yamoah EN, Syka J, Fritzsch B, and Pavlinkova G. (2022) "ISL1 is necessary for auditory neuron development and contributes towards tonotopic organization."PNAS,119 (37) e2207433119, https://doi.org/10.1073/pnas.2207433119

• Filova I, Bohuslavova R, Tavakoli M, Yamoah EN, Fritzsch B, Pavlinkova G. (2022) "Early Deletion of Neurod1 Alters Neuronal Lineage Potential and Diminishes Neurogenesis in the Inner Ear." Frontiers in Cell and Developmental Biology  https://doi.org/10.3389/fcell.2022.845461

• Magalhaes-Novais, S., Blecha, J., Naraine, R., Mikesova, J., Abaffy, P., Pecinova, A., Milosevic, M., Bohuslavova, R., Prochazka, J., Khan, S., Novotna, E., Sindelka, R., Machan, R., Dewerchin, M., Vlcak, E., Kalucka, J., Stemberkova Hubackova, S., Benda, A., Goveia, J., Mracek, T., Barinka, C., Carmeliet, P., Neuzil, J., Rohlenova, K., and Rohlena, J. (2022). "Mitochondrial respiration supports autophagy to provide stress resistance during quiescence." Autophagy 1-18, doi: 10.1080/15548627.2022.2038898

• Petitpre, Ch., Faure, L., Uhl, P., Fontanet, P., Filova, I., Pavlinkova, G., Adameyko, I., Hadjab, S., Lallemend, F. (2022) „Single-cell RNA-sequencing analysis of the developing mouse inner ear identifies molecular logic of auditory neuron diversification“ Nat Comm 13(3878) doi.org/10.1038/s41467-022-31580-1

2021

• 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

• Zatecka E., Bohuslavova R, Valaskova E, Margaryan H, Elzeinova F, Kubatova A, Hylmarova S, Peknicova J, Pavlinkova G. The Transgenerational Transmission of the Paternal Type 2 Diabetes-Induced Subfertility Phenotype. Frontiers in Endocrinology 5;12:763863. doi: 10.3389/fendo.2021.763863

2020

• 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

2019

• 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.

2018

• 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.

2017

• 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.

2016

• 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.

2015

• 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.

2014

• 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.

2013

• 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.

2011

• 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.

2010

• 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: GA24-10497S, G. Pavlínková: The role of epitranscriptomic regulatory mechanisms in the etiology of congenital heart disease: the effect of hypoxia and sex. 2024 – 2026

GACR: GA23-05963S: Pavlinkova: Transcriptional and epigenetic regulation of auditory neuron development.  2023-2025

GAUK: 260523 PřF B-BIO Mora-Lebron, Laura: Transcriptional and epigenetic roles of NEUROD1 in inner ear neuron development

GACR: GA22-11516S: Pavlinkova: Transcriptional and epigenetic control of pancreas development and function. 2021 - 2024

GAUK: 162522 PřF B-BIO Tavakoli, Mitra: Epigenetická role ISL1 ve vývoji sluchové dráhy

GAUK: 160122 PřF B-BIO Hrabalová, Petra: Úloha HIF-1α v embryonálním vývoji sympatického nervového systému srdce v kombinaci s maternálním diabetem

GAČR: GA21-03847S, G. Pavlínková: Úloha HIF-1α ve vývoji sympatického nervového systému v srdci. 2021-2023.

AZV: NU20J-02-00035, G. Pavlínková: Cardiac ischemic tolerance of chronically hypoxic hearts: the role of hypoxia-inducible factor 1alpha and mitochondria. 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: Transcriptional regulation in neurosensory development and function in the inner ear. 2017-2019.

GAČR: GA16-06825S, G. Pavlínková: Programming of the developing heart by maternal diabetes. 2016-2018.

GAUK: 780216 Funkční role Sox2 v neurosenzorickém vývoji vnitřního ucha. 2016.

GAUK: 228416 Role HIF-1 signalizace v diabetické embryopatii. 2016.

GAČR: GA16-06825S, G. Pavlínková: Programming of the developing heart by maternal diabetes. 2016-2018.

GAUK: 324615 Transkripční regulace během vývoje vnitřního ucha. 2015.

GAČR: GA13-07996S, G. Pavlínková: Molecular mechanisms responsible for generating cellular diversity in the inner ear. 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.