Rosettes in Adrenal Development, Maintenance and Disease

肾上腺皮质不断重塑，以回应生理线索，虽然确切的机制， 控制这一点的机制仍然不太清楚。从我们先前的研究中可以清楚地看出，在产后期间， 在发育过程中，肾上腺皮质经历了区域性转分化， 产生了束状类（zF）。这一过程可能涉及多细胞的形成和分解。 通过粘附连接（AJ）复合体进行粘附。尽管这些结构在调节 尚未评估肾上腺功能以及其调节失调是否会导致疾病。鉴于 原发性醛固酮增多症（PA）是继发性高血压的最常见形式， 扩大zG，进一步研究参与调节zG的因子和/或信号通路 发展和维护是必要的。我们的初步数据，利用b-连环蛋白功能获得性小鼠 模型表明PA中的zG增生是由玫瑰花结分解/转分化的阻断驱动的。在 此外，该阻断涉及FGFR 2信号传导的上调，这似乎是玫瑰花结所需的。 在正常发育过程中。此外，我们还发现，roadmap充当协调中心， 通过AJ复合物的Ca 2+信号传导和随后的醛固酮产生。根据我们最近的发现， 越来越多的证据表明，进一步研究AJs，roxyline和控制它们的信号的作用是必要的。 因此，我们提出以下建议： 目标1.确定AJs和roximal如何调节产后zG发育和功能。 目标2.确定FGFR 2信号传导如何调节出生后zG发育和功能。 目标3。确定roxylase和β-Catenin在成人zG转换和功能中的作用。 这些研究试图了解在出生后期间控制zG功能的调节机制， 开发和维护。这些研究的成功完成将提供关键的见解， 控制zG稳态和PA的启动和进展的机制，这可能导致新的 针对这种疾病的靶向治疗。

The adrenal cortex continuously remodels in response to physiological cues, though the exact mechanisms that controls this remain less well understood. It is clear from our prior studies that during postnatal development, the adrenal cortex undergoes zonal transdifferentiation in which the zona Glomerulosa (zG) gives rise to the zona Fasciculata (zF). This process likely involves formation and resolution of multicellular rosettes via the adherens junction (AJ) complex. Although what role these structures play in the regulation of adrenal function as well as whether their dysregulation leads to disease has not been assessed. Given that primary aldosteronism (PA), the most common form of secondary hypertension, involves hyperplasic expansion of the zG, further study of the factors and/or signaling pathways involved in regulating zG development and maintenance is warranted. Our preliminary data, utilizing a b-catenin gain-of-function mouse model suggest that zG hyperplasia in PA is driven by a block in rosette resolution/transdifferentiation. In addition, this block involves the up-regulation of FGFR2 signaling which appears to be required for rosette formation during normal development. Further, we have found that rosettes act as a coordinating center for Ca2+ signaling, via the AJ complex, and subsequent aldosterone production. Based on our recent findings, it is increasing evident that further study of the role of AJs, rosettes and the signals that control them is warranted. Therefore, we propose the following: Aim 1. Determine how AJs and rosettes regulate postnatal zG development and function. Aim 2. Establish how FGFR2 signaling regulates postnatal zG development and function. Aim 3. Define the role of rosettes and β-Catenin in zG turnover and function in the adult. These studies seek to understand the regulatory mechanisms that control zG function during postnatal development and maintenance. The successful completion of these studies will provide critical insights into the mechanisms that govern zG homeostasis and the initiation and progression of PA, which may lead to new targeted therapies for this disease.