Mechanisms of the adrenal medulla stress response.

肾上腺髓质应激反应的机制。

• 批准号: 7009604
• 负责人: Corey B Smith
• 金额: $ 31.09万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-02-01 至 2009-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7009604
• 关键词: binding sites; calcium flux; catecholamines; charge coupled device camera; chemical kinetics; chromaffin cells; dynamin; electrochemistry; endocytosis; exocytosis; fluorescent dye /probe; fluorimetry; immunocytochemistry; intracellular membranes; intracellular transport; laboratory mouse; neuroendocrine system; neuroregulation; neurotransmitter transport; stress; sympathetic nervous system; tissue /cell culture; transfection; vesicle /vacuole; voltage /patch clamp

DESCRIPTION (provided by applicant): Stress is a physiological response of the sympathetic nervous system to environmental pressures. If left unchecked it can lead to patho-physiologies such as hypertension and diabetes. Chromaffin cells of the adrenal medulla are a primary endocrine output of the sympathetic nervous system and secrete a host of transmitter molecules, including catecholamines and peptide transmitters, through the fusion of dense core secretory granules. At basal firing rates, set by the sympathetic tone, catecholamine output regulates homeostatic processes such as enteric function, vascular tone and insulin secretion. Stress-mediated sympathetic activation leads to elevated catecholamine secretion, increasing cardiac output and glucagon levels. Stress also evokes peptide transmitter release, including enkephalin which acts as an analgesic and allows the organism to focus on escape and defense. Our goal is to understand how chromaffin cells regulate the release of catecholamine and signaling peptides under physiological basal-firing and stress activation. Cellular mechanisms for catecholamine release have been studied, but peptide transmitter release is less well understood under these conditions. In this proposal we will test that, under basal firing, chromaffin granules undergo a restricted fusion with the cell surface and selectively release catecholamine. We will test that stress-activation induces a full fusion and collapse of the granule leading to release of both catecholamine and peptide cargos. We will employ electrophysiological, electrochemical, fluorescence imaging, immunocytochemical and biochemical approaches. We will test for exocytosis of catecholamine and protein cargo from chromaffin granules under basal-firing and stress-activated states. We will test the roles of key molecules in the exo-endocytic mechanism and we will measure the degree granule collapse into the cell surface during the exo-endocytic cycle. This data will provide a fundamental understanding of the cellular and molecular mechanisms for the endocrine stress response in chromaffin cells.

描述（由申请人提供）：压力是交感神经系统对环境压力的生理反应。如果不选中，则可能导致病情生理学，例如高血压和糖尿病。肾上腺髓质的铬蛋白细胞是交感神经系统的主要内分泌输出，并通过融合密集的核心分泌颗粒来分泌许多发射机分子，包括儿茶酚胺和肽发射机。在基础发射速率下，通过交感神经调节，儿茶酚胺输出调节体内稳态过程，例如肠功能，血管张力和胰岛素分泌。压力介导的交感神经激活导致儿茶酚胺分泌升高，心输出量和胰高血糖素水平升高。压力还唤起了肽发射器的释放，包括充当镇痛药的Enkephalin，并使生物体能够专注于逃生和防御。我们的目标是了解铬蛋白细胞如何调节在生理基础射击和应激激活下释放儿茶酚胺和信号肽的释放。已经研究了儿茶酚胺释放的细胞机制，但是在这些条件下，肽发射器释放的理解较低。在此提案中，我们将测试，在基础发射下，铬蛋白颗粒会与细胞表面受到限制的融合并有选择性释放儿茶酚胺。我们将测试应力激活会诱导颗粒的完全融合和塌陷，从而释放儿茶酚胺和肽肉类。我们将采用电生理，电化学，荧光成像，免疫细胞化学和生化方法。我们将测试来自基础进攻和应激激活态下铬蛋白颗粒的儿茶酚胺和蛋白质货物的胞吐作用。我们将测试关键分子在外胞吞机制中的作用，并将在外核细胞周期中测量颗粒塌陷到细胞表面。该数据将提供对铬蛋白细胞内分泌应激反应的细胞和分子机制的基本理解。