Molecular Regulation of Adrenal Cortex Homeostasis and Remodeling

描述（由申请人提供）：肾上腺皮质在整个出生后的生活中产生类固醇激素，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，大脑皮层会对这些输入的长期变化做出反应。虽然肾上腺皮质干细胞或祖细胞群可能对稳态和重塑系统有贡献，并受其调节，但这些细胞的分子身份、它们在腺体中的位置以及控制其行为的肾上腺内信号回路却知之甚少。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感兴趣的问题。Sonic hedgehog （Shh）通路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。初步的实验假设Shh通路在肾上腺皮质的发育、维持和重塑中起着关键作用，并确定了多个肾上腺皮质祖细胞和/或干细胞群体。这些假设将通过三个目标在小鼠模型中进行测试。在第一个Aim中，对肾上腺皮质Shh通路活性的操作将测试Shh信号在肾上腺中发挥多种作用的假设，包括调节胶囊的生长和维持，调节类固醇细胞分化和控制胶囊产生的互惠信号。在第二个目标中，小鼠遗传谱系追踪实验将测试产生或接收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。第三个目标将使用两种实验范式-饮食盐操纵和慢性促肾上腺皮质激素或地塞米松管理-来解决Shh通路活性和腺体重塑之间的功能关系，以验证动态hedgehog信号影响皮质重塑的假设，以及生理输入调节Shh通路活性并调节由Shh信号识别的祖细胞的命运。总之，这些实验将通过探索影响这一重要腺体维持和重塑的新分子机制来推进我们对肾上腺生物学的理解。它们也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。

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.