Molecular Regulation of Adrenal Cortex Homeostasis and Remodeling

描述(申请人提供)：肾上腺皮质在出生后的整个生命中都会产生类固醇激素，以应对压力和其他生理输入。大脑皮层的内分泌细胞不断得到补充，大脑皮层根据这些输入的长期变化进行重塑。虽然可能存在有助于内环境平衡和重塑系统并受其调控的肾上腺皮质干或祖细胞群，但这些细胞的分子身份、它们在腺体中的位置以及控制它们行为的肾上腺内信号通路仍然知之甚少。长期目标是了解控制肾上腺皮质如何维持和重塑的分子和细胞逻辑，这是一个从基础和临床科学角度都感兴趣的问题。Sonic Hedgehog(Shh)途径被认为是肾上腺生长和重塑的潜在调节因子，也是肾上腺皮质祖细胞和/或干细胞群体的标志物。初步实验提出Shh通路在肾上腺皮质发育、维持和重塑中起关键作用的假设，并鉴定出多个肾上腺皮质前体和/或干细胞群。这些假说将通过三个目标在小鼠模型中进行验证。在第一个目标中，对肾上腺皮质Shh通路活性的操作将检验Shh信号在肾上腺中发挥多种作用的假设，包括调节被膜的生长和维持，调节类固醇生成细胞的分化，以及控制被膜产生的相互作用的信号。在第二个目标中，小鼠基因谱系追踪实验将检验产生或接收Shh信号的肾上腺皮质细胞具有祖细胞或干细胞特性的假设。第三个目标是研究Shh途径活性和腺体重塑之间的功能关系，使用两个实验范例--食盐操作和慢性给药促肾上腺皮质激素或地塞米松--以验证动态刺猬信号影响皮质重塑以及生理输入调节Shh途径活性和调节Shh信号识别的前体细胞命运的假说。总之，这些实验将通过探索影响这个重要腺体的维持和重塑的新的分子机制来促进我们对肾上腺生物学的理解。它们还将更广泛地有助于我们理解信号系统和动物生理学之间的接口。与公共卫生相关：肾上腺的皮质或外部区域在整个生命过程中都会产生类固醇激素；如果激素生产因基因突变而中断，就像大约1：15000的人所发生的那样，如果不进行终身的每日激素替代治疗，它是致命的。这个项目将研究维持肾上腺皮质中产生类固醇的细胞的分子机制。更多地了解这些机制可能会改善肾上腺疾病的管理，最终可能会通过基因修复和细胞替代疗法来治疗患者。

DESCRIPTION (provided by applicant): The adrenal cortex produces steroid hormones throughout postnatal life in response to stress and other physiological inputs. The endocrine cells of the cortex are constantly replenished, and the cortex remodels in response to prolonged changes in these inputs. While adrenocortical stem or progenitor populations that contribute to, and are regulated by, homeostatic and remodeling systems likely exist, the molecular identity of these cells, their location within the gland, and the intraadrenal signaling circuits that control their behavior are very poorly understood. The long-term goal is to understand the molecular and cellular logic that controls how the adrenal cortex is maintained and remodeled, an issue of interest from both basic and clinical scientific perspectives. The Sonic hedgehog (Shh) pathway was identified as a potential regulator of adrenal growth and remodeling, and a marker of adrenocortical progenitor and/or stem cell populations. Preliminary experiments led to the hypotheses that the Shh pathway plays critical roles in adrenocortical development, maintenance and remodeling, and identifies multiple adrenocortical progenitor and/or stem populations. These hypotheses will be tested in mouse models through three Aims. In the first Aim manipulations of Shh pathway activity in the adrenal cortex will test the hypotheses that Shh signaling plays multiple roles in the adrenal gland, including regulating capsule growth and maintenance, regulating steroidogenic cell differentiation and controlling a reciprocal signal produced by the capsule. In the second Aim murine genetic lineage tracing experiments will test the hypotheses that the adrenal cortical cells that make or receive the Shh signal have properties of progenitor or stem cells. The third Aim will address the functional relationship between Shh pathway activity and gland remodeling using two experimental paradigms - dietary salt manipulation and chronic adrenocorticotropin or dexamethasone administration- to test the hypothesis that dynamic hedgehog signaling influences cortical remodeling and that physiological inputs regulate Shh pathway activity and modulate the fate of the progenitors identified by Shh signaling. Together these experiments will advance our understanding of adrenal biology by exploring novel molecular mechanisms that influence maintenance and remodeling of this important gland. They also will more broadly contribute to our understanding of the interface between signaling systems and animal physiology. PUBLIC HEALTH RELEVANCE: The cortex, or outer region, of the adrenal gland produces steroid hormones throughout life; if hormone production is disrupted due to genetic mutation, as occurs in about 1:15000 people, it is lethal without lifelong daily hormone replacement therapy. This project will study the molecular mechanisms that maintain the cells in the adrenal cortex that produce steroids. Greater understanding of these mechanisms may lead to improved management of adrenal disorders and ultimately perhaps ways to treat patients by gene repair and cell replacement therapy.