Rosettes in Adrenal Development, Maintenance and Disease

肾上腺皮质对生理信号的反应持续重塑，尽管确切的机制是 控制这一点的因素仍然鲜为人知。从我们之前的研究中可以清楚地看出，在出生后 在发育过程中，肾上腺皮质经历了带状转分化，其中肾小球带(Zg) 形成束状带(ZF)。这一过程可能涉及多细胞的形成和分解。 通过附着连接(AJ)复合体形成的玫瑰花环。虽然这些结构在调节生物多样性方面起到了什么作用 肾上腺功能以及它们的失调是否会导致疾病还没有得到评估。考虑到 原发性醛固酮增多症(PA)是继发性高血压最常见的形式，涉及增生性疾病 ZG的扩展，进一步研究参与ZG调节的因子和/或信号通路 开发和维护是有保证的。我们的初步数据，利用b-连环蛋白功能增益小鼠 模型表明，PA中ZG的增殖是由玫瑰花结分辨率/转分化障碍所致。在……里面 此外，这种阻断涉及FGFR2信号的上调，这似乎是玫瑰花结所必需的 在正常发育过程中形成。此外，我们还发现，玫瑰花环起着协调中心的作用 CA2信号，通过AJ复合体，以及随后的醛固酮产生。根据我们最近的发现， 越来越多的证据表明，有必要进一步研究AJ、玫瑰花环和控制它们的信号的作用。 因此，我们提出以下建议： 目的1.确定AJs和玫瑰花环如何调节出生后ZG的发育和功能。 目的2.确定FGFR2信号如何调节出生后ZG的发育和功能。 目的3.明确玫瑰花环和β-连环蛋白在成人ZG代谢和功能中的作用。 这些研究试图了解在出生后控制zg功能的调节机制。 开发和维护。这些研究的成功完成将为 控制ZG动态平衡和PA的启动和进展的机制可能导致新的 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.