Steroid hormones to control sex development, metabolism, stress response, blood pressure and body composition. Steroid hormones synthesis and action is conserved across species. The importance of cofactors in the function of steroidogenic enzymes has become apparent during recent years. Data from in vitro research suggests important regulatory capacity of co-factors significantly influencing total steroid hormone production. However, the significance of these mechanisms in vivo remains elusive. Our central hypothesis is that cofactor regulation of mitochondrial cytochrome P450 enzymes is a key regulatory mechanism of steroidogenesis. Thus, following a novel approach to address these unanswered research questions, this project will address these questions in zebrafish. This will have the advantage that consequences of disrupted steroidogenesis can be easily studied in embryos and in adult animals. Two zebrafish models will be used to dissect the first and rate limiting step of steroidogenesis by disrupting the enzymatic function as well as the cofactor function. Comparing these two models will provide novel mechanistic insights into the regulation of the crucial step of steroidogenesis. Since this can have vital consequences on the developing and adult organisms, we will conduct in vivo studies analysing the response of regulatory pathways to differentially disrupted steroidogenesis. In addition, we will study the impact of cofactor modifications on steroidogenesis to explore novel mechanisms regulating key parts of steroidogenesis. Thus this project will lead to a better understanding of the fundamental mechanisms underlying the regulation of steroidogenesis. This will provide novel insights into physiological processes and fundamental pathways during development and adult life. Finally, the identification of new interactions is highly likely, which can be targeted for development of novel antihypertensive drugs and substances modulating stress response.
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