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

描述(申请人提供)：哺乳动物肾上腺的内侧区域由交感神经元组成，释放儿茶酚胺激素肾上腺素和去甲肾上腺素进入血液。在战斗或逃跑的反应中，这些荷尔蒙从肾上腺释放出来，为有机体应对可能对循环、呼吸、肌肉骨骼和代谢控制系统施加的突然需求做好准备。与他们广泛的行动一致的是，肾上腺的不适当活动与各种疾病有关。这些疾病包括高血压(肾上腺过度活动)和糖尿病(肾上腺反应不足)。这项拟议研究的长期目标是确定正常情况下控制这些肾上腺激素释放的机制。一种控制途径被认为是由递质的分泌产生的，这些递质与儿茶酚胺共同释放，并在腺体本身内部调节一个“短反馈回路”。这些联合传播者的身份和他们获释的条件(S)尚不清楚。然而，一个强有力的候选者是神经肽Y，这是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，其释放介导了调节儿茶酚胺分泌的短反馈回路。为了验证这一假设，我们有三个特定的目标，我们将使用小鼠交感神经元(嗜铬细胞)和肾上腺切片来解决。在第一组实验中，我们将测试NPY的净作用是增加儿茶酚胺分泌的想法。我们的第二个特定目标是确定NPY的释放是否能够以自分泌(细胞受限)的方式调节儿茶酚胺的释放。在第三组实验中，我们将测试NPY也可以通过改变突触前输入的强度来调节儿茶酚胺分泌的假设，突触前输入通常限制儿茶酚胺的分泌。通过使用体外和原位准备以及使用电生理和分子技术，我们将全面检验局部反馈途径控制儿茶酚胺分泌的假设。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的激素释放。项目叙事 肾上腺内侧区域分泌调节血液的荷尔蒙 压力和新陈代谢。了解这些分子的释放是如何 受控是需要的，以开发可以纠正他们的 不适当的或过度的释放。

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. These include hypertension (adrenal over-activity) and diabetes (adrenal under-responsiveness). 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 arise from the secretion of transmitters that are co-released with the catecholamines and that mediate a "short feedback loop" within the gland itself. The identity 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 a short feedback loop that regulates 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 idea that the net effect of NPY is to increase the secretion of the catecholamines. Our second specific aim is to determine whether the release of NPY can regulate catecholamine release 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 test the hypothesis that a local feedback pathway controls 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. Project Narrative The inner region of the adrenal gland secretes hormones that regulate blood pressure and metabolism. Understanding how the release of these molecules is controlled is needed for the development of treatments that could correct their inappropriate or excessive release.