Understanding the systemic consequences of disrupted steroidogenesis

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Steroid hormones are key regulators of sex development, behaviour, body homeostasis and metabolism. Deficiencies of steroid synthesis and action are common causes of disorders of sex development (DSD) and congenital adrenal hyperplasia (CAH). The major translational challenge in steroid endocrinology is a substantial lack of understanding of systemic consequences and the brain phenotype associated with CAH and other DSDs. Thus, the aim of this project is to define pathophysiologic consequences of genetically disrupted steroid synthesis and action. We will use novel zebrafish models disrupting different steps of steroidogenesis and its regulation including, 21-hydroxylase and ferredoxin, the key co-factor for mitochondrial steroidogenesis. This work will be complemented by the development of lines deficient for P450 side chain cleavage, 17-hydroxylase and 11-hydroxylase. All models lead to significant differences in the steroid metabolome. Firstly, we will study disrupted redox regulation of steroidogenesis. Thereby, we will dissect the global consequences caused by glucocorticoid deficiency and effects directly attributable to the disrupted redox chain. This will provide fundamental insights into the regulation of mitochondrial steroidogenesis and will lead to a better understanding of the aging process of the adrenal gland. Secondly, this project will model the systemic response to deficient steroidogenesis. We will for the first time define disease specific changes of body homeostasis. These results will profoundly influence our understanding of the molecular pathogenesis of inborn errors of steroidogenesis. This work has the translational potential creating more physiological and effective personalised therapies tailored to specific molecular defects of particular conditions. In addition, gaining novel insights into the system response will significantly improve the understanding of common disease such as hypertension and the metabolic syndrome. Thirdly, this project will explore the role of steroidogenic enzymes in the brain. We will define the effects of disrupted steroidogenic enzymes on neurosteroidogenesis as well as modulation of brain development and function. These studies will for the first time model vital translational questions regarding pathophysiologic problems in inborn errors of steroidogenesis. Thereby, we will establish therapeutic targets to brain anomalies resulting in psychological problems in patients suffering from those conditions. We will use our insights into central nervous pathophysiology to explore their use in psychiatric and stress research. In summary, this project will explore novel avenues in translational research relevant to health and disease employing numerous cutting edge approaches. This research will significantly improve the understanding of the role of glucocorticoids on the whole organism and will be highly relevant to related fields such as stress research, addiction and brain remodelling.