Neuropeptide Y and the Control of Catecholamine Secretion from the Adrenal Gland

描述（由申请人提供）：哺乳动物肾上腺的内部区域由交感神经元组成，交感神经元将儿茶酚胺激素、肾上腺素和去甲肾上腺素释放到血液中。在战斗或逃跑反应期间，这些激素从肾上腺释放出来，并为生物体提供可能对循环，呼吸，肌肉骨骼和代谢控制系统提出的突然要求。与它们广泛的作用相一致，肾上腺的不适当活动与包括高血压在内的各种疾病有关。这项研究的长期目标是确定通常控制这些肾上腺激素释放的机制。一种控制途径被认为涉及与儿茶酚胺共同释放的递质的分泌，并且介导腺体本身内的“短反馈回路”。这些共发射者的身份及其释放条件尚不清楚。然而，一个强有力的候选者是神经肽Y，一种由嗜铬细胞合成的多肽。我们的假设是，神经肽Y是一种肾上腺神经递质，其释放介导调节儿茶酚胺分泌的短反馈回路。为了验证这一假设，我们有3个具体的目标，我们将解决使用小鼠交感神经元（嗜铬细胞）和肾上腺切片。在第一组实验中，我们将检验NPY的净效应是增加儿茶酚胺分泌的假设。我们的第二个具体目标是测试的假设，释放的神经肽Y可以调节儿茶酚胺分泌的自分泌（细胞有限）的方式。在第三组实验中，我们将测试的假设，神经肽Y也可以通过改变的强度，通常限制儿茶酚胺分泌的突触前输入调节儿茶酚胺分泌。通过使用在体外和原位制剂，并采用电生理和分子技术，我们将全面确定是否局部反馈途径控制儿茶酚胺分泌。虽然这项工作研究了肾上腺的调节，但类似的机制可能控制许多不同类型的内分泌组织释放激素。公共卫生相关性：肾上腺的内部区域分泌调节血压和心血管系统的激素。了解这些分子的释放是如何控制的，对于开发可以纠正其不适当或过度释放的治疗方法是必要的。

DESCRIPTION (provided by applicant): The inner region of the mammalian adrenal gland is composed of sympathetic neurons that release the catecholamine hormones, epinephrine and norepinephrine, into the blood. During the fight-or-flight response, these hormones are released from the adrenal gland and prime the organism for the sudden demands that may be placed upon the circulatory, respiratory, musculoskeletal and metabolic control systems. Consistent with their wide-reaching actions, the inappropriate activity of the adrenal gland has been associated with a variety of diseases including hypertension. The long-term objective of the proposed study is to determine the mechanisms that normally control the release of these adrenal hormones. One control pathway is believed to involve the secretion of transmitters that are co-released with the catecholamines and that mediate "short feedback loops" within the gland itself. The identity of these co-transmitters and the condition(s) under which they released are not clear. However one strong candidate is neuropeptide Y, a polypeptide that is synthesized by chromaffin cells. Our hypothesis is that neuropeptide Y is an adrenal neurotransmitter whose release mediates short feedback loops that regulate catecholamine secretion. To test this hypothesis we have 3 specific aims that we will address using murine sympathetic neurons (chromaffin cells) and adrenal slices. In the first set of experiments we will test the hypothesis that the net effect of NPY is to increase the secretion of the catecholamines. Our second specific aim is to test the hypothesis that the release of NPY can regulate catecholamine secretion in an autocrine (cell-limited) manner. In the third set of experiments we will test the hypothesis that NPY can also regulate catecholamine secretion by altering the strength of the pre-synaptic input that normally limits catecholamine secretion. By using in vitro and in situ preparations and by employing electrophysiological and molecular techniques we will comprehensively determine whether local feedback pathways control catecholamine secretion. Although this work examines the regulation of the adrenal gland, similar mechanisms are likely to control the release of hormones from many different types of endocrine tissue. PUBLIC HEALTH RELEVANCE: The inner region of the adrenal gland secretes hormones that regulate blood pressure and the cardiovascular system. Understanding how the release of these molecules is controlled is needed for the development of treatments that could correct their inappropriate or excessive release.