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Molecular Mechanisms in Diabetic Embryopathy

Final Report Summary - DIABETIC EMBRYOPATHY (Molecular Mechanisms in Diabetic Embryopathy)

The proposed reintegration objectives have been achieved via my appointment as a head of the laboratory of molecular pathogenetics at the institute of biotechnology of the academy of sciences of the Czech republic

(http://www.ibt.cas.cz/en/content/showPage/laboratory-of-molecular-pathogenetics-79).

Integration activities:
1) Establishment of the research team: I have built a new research team, which is presently composed of one postdoctoral fellow, three master students, one technician, one senior researcher, and myself. I have directly transferred my knowledge and experience to all members of my research team and to four bachelor students in the form of training and teaching.
2) Integration into the European Union (EU) scientific community: In four years of the international reintegration grants (IRG) project, I have been actively involved in the Czech and European research community by (a) presenting results of my research at conferences, scientific seminars, and invited talks; (b) acting as an external opponent in phD and master programs at Charles university in Prague; and (c) participating in the management of the institute of biotechnology as an internal member of its council. Furthermore, the institute of biotechnology is one of the participating partners in the new European centres of excellence - Biocev. Since August 2009, I have been a Biocev Board member on behalf of the Institute of Biotechnology.
3) Transfer of my knowledge and experience in the form of training, teaching and collaborative research projects: In addition to transferring my existing research project on diabetes from the United States (US) to the EU, I have also transferred my accumulated knowledge and experience in diabetic research. I have launched several new collaborative research projects with EU researchers including: (i) a new research project on neural tube defects, which is supported by the Bo Hjelt foundation for Spina Bifida and by the international federation for Spina Bifida and Hydrocephalus; and new research project with (ii) Prof F. Kolar, the department of developmental cardiology of the institute of physiology, AS CR; (iii) Prof J. Syka, institute of experimental medicine, AS CR; (iv) doc. J. Peknicova, the laboratory of reproductive biology of the institute of biotechnology, AS CR. Additionally, I have also started (v) a collaboration with Dr Ales Tichopad, technical university Munich, Freising-Weihenstephan, Germany.

The most significant scientific results and conclusions:
1) The overarching goal of this research has been to identify key molecular players in the pathogenesis of cardiovascular pathologies caused by the exposure to diabetes. We have analysed changes induced by intrauterine diabetic environment in the developing embryonic heart. Diabetes-exposed embryos showed an increased incidence of cardiac malformations by 28 % compared to embryos from non-diabetic pregnancies. Using the mouse as an experimental system and global gene expression profiling, we have identified target genes, which can serve as an indicator for specific abnormalities in heart development and function, and genes, contributing to developmental heart defects in diabetic pregnancies and heart dysfunctions in the adult. Results of this research were presented at the 51th annual meeting of the teratology society (Pavlinkova, G., Bohuslavova R., Kuthanova L., Sedmera, D., Bloudickova, S. Molecular changes induced by the teratogenic environment of maternal diabetes in embryonic hearts. Birth defects research part A: Clinical and molecular teratology May 2011, 91(5): 339).
2) Next, we demonstrated that exposure to maternal diabetes resulted in dysregulation of the hypoxia-inducible factor 1 (HIF-1) pathway in the developing embryo. For the first time, we linked HIF-1-regulated pathways and the development of congenital malformations in diabetes-exposed embryos. We showed that the environmental (maternal diabetes) and genetic (Hif1a mutation) factors reduce HIF-1 activity in embryos and result in cardiovascular malformations. Results of this research were selected for the platform presentation at the 49th annual meeting of the Teratology Society, Puerto Rico, 2009; and the 52nd annual meeting of the teratology society, USA, 2012. They were subsequently published: 1) Pavlinkova, G., Bohuslavova, R., Sedmera, D., Skvorova, L. Partial HIF-1a Deficiency increases risk of diabetic embryopathy. Birth defects research part A: Clinical and molecular teratology May 2012, 94(5):319, 2012. 2) Pavlinkova, G, Kappen, C., Bohuslavova, R., Salbaum, M. Role of HIF1 pathways in diabetic embryopathy. Birth defects research part A – Clinical and molecular teratology 2009, 85(5):413. The full article has been submitted for publication to journal of molecular and cellular cardiology (#JMCC7092).
3) Additionally, we have analysed the role of HIF1 pathways in responses to the conditions of hypoxia in the adult heart. We have performed gene expression profiling of Hif1a partially deficient adult mutant mice. In contrast to non-mutant mice, sustained hypoxia activates the transcriptional responses of the majority of analysed genes in the Hif1a mutant left ventricle. Our results show that gene expression was differently regulated in the right and left heart ventricles and that it was significantly affected by hypoxia, gender, and Hif1a partial deficiency. The results were published in journal of applied physiology in 2010 (Bohuslavova, R., Kolar, F., Kuthanova, L., Neckar, J., Tichopad, A., Pavlinkova, G.: Gene expression profiling of gender differences in HIF1-dependent adaptive cardiac responses to chronic hypoxia. J. Appl. Physiol. 2010 Oct;109(4):1195-202. )
4) Subsequently, we were interested in the early molecular and physiological changes induced by diabetes and a possible role of HIF1 pathways in cardiac responses to diabetes in the adult heart. We investigated the cardiac responses to diabetic conditions, including changes in left-ventricular (LV) echocardiographic parameters, tissues remodeling, and transcriptional profile modulations in the adult heart. For the first time, we showed that HIF1 pathways are involved in the early manifestation of pathological changes induced by diabetic environment in the heart. Furthermore, impaired HIF1 regulation accelerated the progress of pathological changes in the diabetic heart. Our observations are in line with increasing evidence that HIF1-regulated system is compromised in the diabetic heart (manuscript in preparation).
5) I received the additional funding for my research (i) from the Czech science foundation (GA301/09/0117, 2009-2013); and (ii) from the Czech ministry of education, youth and sports (CZ.1.07/2.3.00/30.0020 2012-2015).

Socio-economic impact of the project:

My research significantly contributes to the better understanding of pathologies associated with diabetes and to the development of strategies for early diagnosis of diabetes. This, in turn, contributes to the on-going efforts of the research community to develop strategies for prevention and early diagnosis of diabetes, in order to minimise its future medical, social and economic costs. This research is extremely important because diabetes and its related complications are the fourth leading cause of death in Europe and health and social welfare costs associated with diabetes already represent an enormous economic burden for the EU countries. Additionally, the reintegration allowed me to launch a high quality academic career in Europe after my return from the US.