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正确维持身体稳态至关重要，但持续的交感体液激活是非常有害的，会导致包括心力衰竭（HF）在内的多种流行疾病。尽管有这些证据，但仍然缺乏对生理和病理条件下神经体液反应基本机制的全面了解。下丘脑室旁核（PVN）和视上核（SON）在交感体液反应的产生中发挥着关键作用，并且越来越多的证据支持心衰动物模型中这些核团的神经元活动升高。然而，确切的潜在机制仍不完全清楚。非典型气体神经递质，特别是一氧化氮（NO），被认为是大脑中关键的抑制信号分子，主要分布在涉及自主/神经内分泌整合的区域。事实上，NO 功能减弱已被证明有助于心力衰竭中交感体液的激活。在这里，我们提出气体分子一氧化碳 (CO) 作为 SON/PVN 内的一种新型信号机制。我们获得的初步结果表明，与 NO 相反，CO 可以刺激下丘脑神经元功能。因此，我们提出了一个新概念，即两种相反的气体分子之间的平衡对于确定下丘脑的神经体液流出至关重要。利用体外电生理学、细胞成像、纤维束示踪和免疫组织化学相结合的多学科方法，我们将检验以下中心假设：CO 生物利用度升高导致心衰时 SON/PVN 神经元活动加剧，而这些影响是通过削弱 NO 抑制功能介导的。我们将在 2 个具体目标中测试我们的中心假设： 1 - 确定假手术大鼠和 HF 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 - 确定假手术大鼠和心力衰竭大鼠 SON/PVN 内 CO 的细胞靶标和作用机制。我们的工作假设是，CO 是一种针对神经分泌神经元和前交感神经元的兴奋性气体分子。我们期望 R21 提案的结果能够提供概念证明，即 CO 是在 SON 和 PVN 内内源产生的，并且它是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影响神经元活动的改变，从而改变心力衰竭动物模型中的神经体液输出。我们相信，这些知识将拓宽我们对下丘脑体内平衡控制的基本细胞机制的理解，以及这些机制的变化如何导致人类流行疾病的病理过程。 公共卫生相关性：心力衰竭是美国的一个主要公共卫生问题，其特点是神经内分泌和自主系统活动增加（神经体液激活），这强烈影响这些患者的发病率和死亡率。然而，神经体液的确切机制仍然未知。在本提案中，我们将使用多学科方法来测试一系列新颖的假设，旨在阐明 中枢神经系统内的信号传导机制有助于心力衰竭中的神经体液激活。我们希望我们的工作能够提供有关心力衰竭患者神经元功能改变的机制的新信息，并帮助开发治疗这种普遍疾病的新颖且更有效的治疗策略。