CO regulation of hypothalamic neuronal activity in health and disease states

健康和疾病状态下丘脑神经元活动的 CO 调节

• 批准号: 8282375
• 负责人: Javier E Stern
• 金额: $ 22.46万
• 依托单位: AUGUSTA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-16 至 2014-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8282375
• 关键词: Angiotensin II; Animal Model; Area; Astrocytes; Biological Availability; Brain; Brain region; Carbon Monoxide; Cell Nucleus; Cells; Congestive Heart Failure; Data; Development; Disease; Disinhibition; Electrophysiology (science); Enzymes; Equilibrium; Fluorescent Dyes; Gases; Generations; Goals; Health; Heart failure; Heme; Homeostasis; Hypothalamic structure; Immunohistochemistry; In Vitro; Knowledge; Lead; Maintenance; Measures; Mediating; Microglia; Modeling; Monitor; Morbidity - disease rate; Neuraxis; Neurons; Neurosecretory Systems; Neurotransmitters; Nitric Oxide; Output; Oxygenases; Pathologic Processes; Patients; Peripheral; Physiological; Plasma; Play; Population; Prevention; Production; Public Health; Rattus; Regulation; Reporting; Role; Series; Signal Transduction; Signaling Molecule; Source; System; Testing; Therapeutic; Vasopressins; Work; cellular imaging; cellular targeting; complement C2a; disease characteristic; gamma-Aminobutyric Acid; human disease; interdisciplinary approach; mortality; novel; paraventricular nucleus; patch clamp; response; treatment strategy

DESCRIPTION (provided by applicant): While coordinated activities of the sympathetic and neuroendocrine systems are essential for proper maintenance of bodily homeostasis, sustained sympathohumoral activation is highly detrimental, contributing to several prevalent diseases, including heart failure (HF). Despite this evidence, a comprehensive understanding of the basic mechanisms underlying neurohumoral responses both in physiological and pathological conditions is still missing. The hypothalamic paraventricular (PVN) and supraoptic (SON) nuclei play pivotal roles in the generation of sympathohumoral responses, and accumulating evidence supports elevated neuronal activity in these nuclei in animal models of HF. However, the precise underlying mechanisms remain incompletely understood. The atypical gas neurotransmitters, particularly nitric oxide (NO), are recognized as critical inhibitory signaling molecules in the brain, mostly in areas involved in autonomic/neuroendocrine integration. In fact, a blunted NO function has been shown to contribute to sympathohumoral activation in HF. Here, we propose the gas molecule carbon monoxide (CO) as a novel signaling mechanism within the SON/PVN. We obtained preliminary results showing that in opposition to NO, CO stimulates hypothalamic neuronal function. Thus, we put forward the novel concept that a balance between two opposing gas molecules is critical in determining neurohumoral outflows from the hypothalamus. Using a multidisciplinary approach combining in vitro electrophysiology, cell imaging, tract tracing and immunohistochemistry, we will test the central hypothesis that elevated CO bioavailability contributes to exacerbated SON/PVN neuronal activity in HF, and that these effects are mediated by blunting NO inhibitory function. We will test our central hypothesis in 2 specific aims: 1 - To determine the specific cellular sources of CO within the SON/PVN in sham and HF rats. Our working hypothesis is that the CO-synthetizing enzyme heme-oxygenase (HO) is expressed in specific cell populations within the SON/PVN, and that an elevated expression occurs in HF rats. 2 - To determine the cellular targets and mechanisms of action of CO within the SON/PVN in sham and HF rats. Our working hypothesis is that CO is an excitatory gas molecule targeting both neurosecretory and presympathetic neurons. We expect results from this R21 proposal to provide the proof-of-concept that CO is endogenously produced within the SON and PVN, and that it is a functionally relevant gas molecule influencing neuronal activity in these brain regions. We will begin to understand how changes in CO/NO interactions contribute to altered neuronal activity, and consequently neurohumoral output in an animal model of HF. We believe this knowledge will broaden our understanding of basic cellular mechanisms contributing to the hypothalamic control of homeostasis, as well as how changes in these mechanisms lead to pathological process in prevalent human diseases. PUBLIC HEALTH RELEVANCE: Heart failure, a major public health problem in the USA, is characterized by increased activity of the neuroendocrine and autonomic systems (neurohumoral activation), which strongly influences morbidity and mortality in these patients. However, the precise mechanisms underlying neurohumoral remain unknown. In this proposal, we will use a multidisciplinary approach to test a series of novel hypothesis that aim to elucidate signaling mechanisms within the central nervous system that contribute to neurohumoral activation in heart failure. We expect our work to provide novel information on mechanisms underlying altered neuronal function in heart failure patients, and to help in the development of novel and more efficient therapeutic strategies for the treatment of this prevalent disease.

描述（由申请人提供）：虽然交感神经和神经内分泌系统的协调活动对于适当维持身体内稳态至关重要，但持续的交感神经体液激活是非常有害的，会导致包括心力衰竭（HF）在内的几种流行疾病。尽管有这些证据，但对生理和病理条件下神经体液反应的基本机制的全面理解仍然缺失。下丘脑室旁核（PVN）和视上核（SON）在交感体液反应的产生中起关键作用，越来越多的证据支持HF动物模型中这些核的神经元活性升高。然而，确切的潜在机制仍然不完全清楚。非典型气体神经递质，特别是一氧化氮（NO），被认为是大脑中重要的抑制信号分子，主要涉及自主神经/神经内分泌整合的区域。事实上，一氧化氮功能减弱已被证明有助于HF的交感病理体液激活。在这里，我们提出气体分子一氧化碳（CO）作为SON/PVN内的一种新的信号传导机制。我们获得的初步结果表明，与NO相反，CO刺激下丘脑神经元功能。因此，我们提出了一个新的概念，即两种相反气体分子之间的平衡是决定下丘脑神经体液流出的关键。采用多学科方法，结合体外电生理学、细胞成像、通道示踪和免疫组织化学，我们将验证CO生物利用度升高导致HF中SON/PVN神经元活性加剧的中心假设，并且这些影响是通过钝化NO抑制功能介导的。我们将在两个特定目标中验证我们的中心假设：1 -确定假手术和心衰大鼠SON/PVN内CO的特定细胞来源。我们的工作假设是co合成酶血红素加氧酶（HO）在SON/PVN内的特定细胞群中表达，并且在HF大鼠中表达升高。2 -确定CO在假手术和心衰大鼠SON/PVN内的细胞靶点和作用机制。我们的工作假设是CO是一种兴奋性气体分子，针对神经分泌和前交感神经元。我们期望这项R21提案的结果能够提供CO在SON和PVN内内源性产生的概念证明，并且它是一种影响这些大脑区域神经元活动的功能相关气体分子。我们将开始了解CO/NO相互作用的变化如何导致HF动物模型中神经元活动的改变，从而导致神经体液输出的改变。我们相信这些知识将扩大我们对下丘脑控制体内平衡的基本细胞机制的理解，以及这些机制的变化如何导致流行人类疾病的病理过程。