Understanding the systemic consequences of disrupted steroidogenesis

了解类固醇生成中断的系统性后果

• 批准号: 329397225
• 负责人: Dr. Nils Krone
• 金额: --
• 依托单位: Medizinische Klinik und Poliklinik III
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2017
• 资助国家: 德国
• 起止时间: 2016-12-31 至 2021-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/329397225?language=en
• 关键词: Understanding; systemic; consequences; disrupted; steroidogenesis

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.

类固醇激素是性发育、行为、体内平衡和新陈代谢的关键调节剂。类固醇合成和作用的缺陷是性发育障碍（DSD）和先天性肾上腺皮质增生（CAH）的常见原因。类固醇内分泌学的主要翻译挑战是对CAH和其他DSD相关的全身性后果和脑表型缺乏了解。因此，本项目的目的是确定遗传破坏类固醇合成和作用的病理生理后果。我们将使用新的斑马鱼模型破坏类固醇生成及其调节的不同步骤，包括21-羟化酶和铁氧还蛋白，线粒体类固醇生成的关键辅因子。这项工作将通过开发缺乏P450侧链裂解、17-羟化酶和11-羟化酶的品系来补充。所有模型导致类固醇代谢组的显着差异。首先，我们将研究类固醇生成的氧化还原调节中断。因此，我们将剖析糖皮质激素缺乏引起的全球后果和直接归因于氧化还原链中断的影响。这将为线粒体类固醇生成的调节提供基本的见解，并将导致更好地了解肾上腺的衰老过程。其次，该项目将模拟类固醇合成不足的全身反应。我们将首次定义疾病特异性的身体内稳态变化。这些结果将深刻地影响我们对类固醇合成先天性缺陷的分子发病机制的理解。这项工作具有转化潜力，可以创造出针对特定条件下特定分子缺陷的更生理和有效的个性化疗法。此外，获得对系统响应的新见解将显着提高对高血压和代谢综合征等常见疾病的理解。第三，本项目将探索类固醇生成酶在大脑中的作用。我们将确定破坏类固醇生成酶对神经类固醇生成的影响以及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性错误的病理生理问题的重要翻译问题。因此，我们将建立治疗目标，大脑异常导致心理问题的患者患有这些条件。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压力研究中的应用。总之，该项目将探索与健康和疾病相关的转化研究的新途径，采用多种尖端方法。这项研究将显著提高对糖皮质激素在整个生物体中作用的理解，并将与压力研究，成瘾和大脑重塑等相关领域高度相关。