Understanding the systemic consequences of disrupted steroidogenesis

类固醇激素是性发育、行为、身体动态平衡和新陈代谢的关键调节器。类固醇合成和作用缺陷是性发育障碍(DSD)和先天性肾上腺增生症(CAH)的常见原因。类固醇内分泌学的主要翻译挑战是对全身性后果以及与CAH和其他DSD相关的大脑表型缺乏了解。因此，这个项目的目的是定义遗传干扰的类固醇合成和作用的病理生理学后果。我们将使用新的斑马鱼模型来扰乱类固醇合成的不同步骤及其调节，包括21-羟基酶和铁氧还蛋白，这是线粒体类固醇合成的关键辅助因子。这项工作将由缺乏P450侧链裂解、17-羟基酶和11-羟基酶的品系的培育来补充。所有的模型都会导致类固醇代谢组的显著差异。首先，我们将研究类固醇合成的氧化还原调节被打乱。因此，我们将剖析糖皮质激素缺乏造成的全球后果以及直接归因于氧化还原链中断的影响。这将为线粒体类固醇合成的调控提供基本的见解，并将有助于更好地了解肾上腺的衰老过程。其次，该项目将模拟系统对激素合成不足的反应。我们将首次定义身体内稳态的疾病特异性变化。这些结果将深刻地影响我们对类固醇生成先天错误的分子发病机制的理解。这项工作具有创造更多生理和有效的个性化治疗的潜力，这些治疗是针对特定条件下的特定分子缺陷量身定做的。此外，对系统反应获得新的见解将显著提高对常见疾病的理解，如高血压和代谢综合征。第三，这个项目将探索类固醇生成酶在大脑中的作用。我们将确定破坏的类固醇合成酶对神经类固醇生成的影响以及对大脑发育和功能的调节。这些研究将首次模拟有关类固醇生成先天错误的病理生理学问题的重要翻译问题。因此，我们将建立治疗目标，以治疗导致患有这些疾病的患者出现心理问题的大脑异常。我们将利用我们对中枢神经病理生理学的见解来探索它们在精神病学和应激研究中的应用。总而言之，该项目将探索与健康和疾病相关的转化研究的新途径，采用许多尖端方法。这项研究将显著提高对糖皮质激素对整个生物体作用的理解，并将与应激研究、成瘾和大脑重塑等相关领域高度相关。

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.