Physiology of the Prolactin Releasing Peptides

描述（由申请人提供）：这是一个修订的竞争性更新申请（HL66023），继续我们对最近描述的神经肽的生理学相关性的检查，我们已经证明至少在药理学上通过脑作用部位刺激应激激素分泌（催乳素，PRL和促肾上腺皮质激素，ACTH）。此外，这些肽刺激应激相关的行为反应（活动），至少有一种肽在大脑中刺激交感神经活动，导致血压升高。这些肽（催乳素释放肽PrRP，神经肽W， NPW和神经肽B， NPB）在大脑中不同的神经元群中产生，其中许多支配下丘脑室旁核（PVN），弓形核（ARC）和下丘脑腹内侧和背内侧核（VMH/DMH）。这三种多肽都包含在支配下丘脑和脑干自主神经中枢的神经元中。我们的目标是了解这些肽在下丘脑和下丘脑外对应激的反应中所起的作用。我们解决了多个具体的目标，所有这些目标都与基本假设有关，即在某些应激模式下，这些肽中的一种或多种对于内分泌和/或心血管对应激的反应是必不可少的。我们的方法将是利用电生理学、药理学和单细胞RT- PCR方法证明这些肽对已识别的前脑和后脑神经元的直接影响[例如PVN、ARC、VMH/DMH、孤束核（NTS）、延髓喙侧（RVLM）和迷走神经背运动核]。然后，我们将尝试折衷肽的产生，并检查激素分泌对身体应激的反应以及心血管对高血压和低血压挑战的反应（即压力反射敏感性）。了解控制压力反应的正常机制将揭示人类压力管理的潜在策略以及压力对心血管和代谢的影响。这些研究可能还有助于了解代谢综合征（X综合征）发展的核心机制，其特征是肥胖、血糖控制不良、代谢和自主神经功能改变以及心血管不良结局的倾向。此外，这些研究将进一步深入了解激素和自主神经对压力的协调反应。

DESCRIPTION (provided by applicant): This is a rerevised, competitive renewal application (HL66023) that continues our examination of the physiologic relevance of recently described neuropeptides which we have demonstrated to act at least pharmacologically to stimulate stress hormone secretion (prolactin, PRL, and adrenocorticotropin, ACTH) by a brain site of action. Additionally, these peptides stimulate stress-related behavioral responses (activity) and at least one acts in brain to stimulate sympathetic activity resulting in increased blood pressure. These peptides (prolactin releasing peptide, PrRP; neuropeptide W, NPW; and neuropeptide B, NPB) are produced in separate populations of neurons in brain, many of which innervate the hypothalamic paraventricular nucleus (PVN), arcuate nucleus (ARC) and ventromedial and dorsomedial hypothalamic nuclei (VMH/DMH). All three peptides are contained in neurons that innervate autonomic centers in hypothalamus and brain stem. It is our goal to understand the roles these peptides play in the hypothalamic and extrahypothalamic responses to stress. We address multiple specific aims all related to the founding hypothesis that one or more of these peptides is essential for the endocrine and/or cardiovascular response to stress, under certain paradigms of stress. Our approach will be to demonstrate direct effects of these peptides on identified fore- and hindbrain neurons [e.g. in PVN, ARC, VMH/DMH, nucleus tractus solitarius (NTS), rostral lateral medulla (RVLM), and dorsal motor nucleus of the Vagus] using electrophysiologic, pharmacologic and single cell RT- PCR approaches. We will then attempt compromise of peptide production and examine hormone secretion in response to physical stress and the cardiovascular response to hypertensive and hypotensive challenge (i.e. baroreflex sensitivity). Understanding the normal mechanisms controlling the response to stress will reveal potential strategies for the management of stress in the human population and the cardiovascular and metabolic consequences of that stress. These studies may also provide insight into the central mechanisms contributing to development of the metabolic syndrome (Syndrome X), which is characterized by obesity, poor glycemic control, altered metabolic and autonomic function and a propensity for adverse cardiovascular outcomes. Additionally, these studies will provide further insight into the coordinated hormonal and autonomic responses to stress.