Rosettes in Adrenal Development, Maintenance and Disease

玫瑰花结在肾上腺发育、维护和疾病中的作用

• 批准号: 10657410
• 负责人: David T Breault
• 金额: $ 65.99万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-19 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10657410
• 关键词: Adherens Junction; Adrenal Cortex; Adrenal Glands; Adrenal hormone preparation; Adult; Affect; Aldosterone; Angiotensin II; Biological Assay; Blood Pressure; Cell-Cell Adhesion; Cells; Clinical; Complex; Cues; Data; Development; Disease; Epithelium; FGFR2 gene; Future; Genetic; High Prevalence; Homeostasis; Hormones; Hyperaldosteronism; Hyperplasia; Hypoaldosteronism; Life; Maintenance; Measures; Mediating; Mediator; Metabolic; Modeling; Molecular; Morphogenesis; Mus; N-Cadherin; Nuclear; Organogenesis; Pathogenesis; Pathway interactions; Patients; Physiologic pulse; Physiological; Play; Process; Production; Proteins; Quantitative Reverse Transcriptase PCR; Regulation; Renin; Resolution; Role; Secondary Hypertension; Signal Pathway; Signal Transduction; Slice; Speed; Stress; Structure; System; Testing; Tissues; Up-Regulation; Western Blotting; Zona Fasciculata; Zona Glomerulosa; alpha catenin; beta catenin; cardiovascular disorder risk; experimental study; gain of function; high risk; hypertensive; in vivo; insight; live cell imaging; loss of function; mouse model; neutralizing monoclonal antibodies; new therapeutic target; postnatal; postnatal development; renal damage; response; transcriptomics; transdifferentiation

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.

肾上腺皮质响应物理线索不断重塑，尽管确切的机制 控制这一点仍然不太了解。从我们先前的研究中可以明显看出，在产后期间 发育，肾上腺皮质经历了Zona glomerulosa（ZG）的区域转分化。 产生Zona fasciculata（ZF）。这个过程可能涉及多细胞的形成和分辨率 通过粘附连接（AJ）复合物的玫瑰花结。尽管这些结构在调节中起着什么作用 肾上腺功能以及它们的失调是否导致疾病尚未评估。鉴于 初级醛固酮（PA）是次级高血压的最常见形式，涉及增生 ZG的扩展，对调节ZG的因素和/或信号通路的进一步研究 有必要进行开发和维护。我们的初步数据，利用B-catenin功能获得的鼠标 模型表明，PA中的ZG增生是由玫瑰花塞分辨率/跨分化的块驱动的。在 此外，该块涉及FGFR2信号的上调，这似乎是玫瑰花结的 正常发育过程中的形成。此外，我们发现Rosettes充当了协调的中心 Ca2+信号传导通过AJ复合物以及随后的醛固酮产生。根据我们最近的发现，这是 越来越多的证据表明，有必要进一步研究AJ，玫瑰花结和控制它们的信号的作用。 因此，我们提出以下内容： 目标1。确定AJ和玫瑰花结如何调节产后ZG的发展和功能。 目标2。确定FGFR2信号如何调节产后ZG的发展和功能。 AIM 3。定义玫瑰花结和β-catenin在ZG周转和功能中的作用。 这些研究试图了解产后控制ZG功能的调节机制 开发和维护。这些研究的成功完成将为您提供关键见解 控制ZG稳态的机制以及PA的主动性和进步，这可能导致新的 针对该疾病的靶向疗法。