Brain MAP Kinases - Substrate for Sympathetic Excitation in Heart Failure

脑 MAP 激酶 - 心力衰竭交感神经兴奋的底物

基本信息

批准号：
8038587
负责人：
Robert B Felder
金额：
$ 37.6万
依托单位：
UNIVERSITY OF IOWA
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-12-15 至 2014-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8038587
关键词：
Acute Age Aldosterone Angiotensin II Animals Astrocytes Automobile Driving Brain Brain region Cardiovascular system Cell Nucleus Cells Characteristics Chronic Complex Development Disease Event Experimental Models Generations Goals Heart failure Hospitalization Hypothalamic structure Individual Inflammation Mediators Inflammatory Interleukin-1 beta Ischemia Knowledge Lead Learning Mediating Mediator of activation protein Microglia Mitogen-Activated Protein Kinases Modeling Molecular Morbidity - disease rate NADP Nerve Neuraxis Neurons Oxidases Oxidation-Reduction Pathway interactions Phenotype Population Process Production Rattus Reactive Oxygen Species Regulation Renin-Angiotensin System Role Signal Pathway Signal Transduction Source Superoxides Sympathetic Nervous System Syndrome System Systolic heart failure TNF gene Techniques Therapeutic Intervention Tumor Necrosis Factor-alpha United States Up-Regulation adverse outcome base brain regulatory center cell type cytokine human MAPK14 protein human old age (65+)hypertensive heart disease macrophage mortality neurochemistry novel novel strategies paraventricular nucleus receptor response statistics stress-activated protein kinase 1 treatment strategy

项目摘要

DESCRIPTION (provided by applicant): Heart failure is the most common reason for hospitalization in the United States among those older than 65 years, and this statistic is expected to grow as the population ages. Over activity of the sympathetic nervous system (SNS) is a cardinal manifestation of the heart failure syndrome, and a strong predictor of morbidity and mortality. Recent studies suggest that altered neurochemical mechanisms in the brain contribute to the augmented SNS activity in heart failure. Several excitatory substances appear in the brain in excess quantities in heart failure. These include angiotensin II (ANG II), aldosterone (ALDO) and the pro-inflammatory cytokines (PIC). All three act to increase the production of reactive oxygen species in the brain, but beyond that it is not at all clear how they activate the SNS. We recently found that blocking one of the three major components of the mitogen-activated protein kinase (MAPK) intracellular signaling cascade in the brain substantially reduced SNS activity in rats with heart failure. These MAPKs are sensitive to the presence of reactive oxygen species, respond to ANG II, ALDO and PIC, and, when activated, lead to the production of more excitatory neurochemical substances that may contribute to persistent activation of the SNS, which is typical of heart failure. The overall goal of this project is to determine to what extent the three major MAPK signaling pathways contribute to the excitatory neurochemical milieu in a key cardiovascular regulatory center of the brain, the paraventricular nucleus of hypothalamus (PVN) that drives SNS activity in heart failure. In rats with systolic heart failure and in normal rats treated with ANG II, ALDO and PIC to induce MAPK activity, we will determine: 1) the effects of the three major MAPK signaling pathways on the expression of excitatory mediators in the PVN; 2) the effects of MAPK signaling in the PVN on SNS activity; 3) the phenotypes of the cells in PVN - neurons, microglia, astrocytes, and perivascular macrophages - that express MAPK signaling, and their influences on the production of excitatory mediators and sympathetic excitation. A combination of molecular, immunohistochemical, and electrophysiological techniques will be used to elucidate the mechanisms by which brain MAPK signaling influences SNS activity. We hope these studies will identify novel targets for therapeutic intervention in systolic heart failure. PUBLIC HEALTH RELEVANCE: This project examines the role of a critical intracellular signaling mechanism, the mitogen-activated protein kinases, in the upregulation of excitatory mediators (angiotensin II, aldosterone, and pro-inflammatory cytokines) in the brain, and the subsequent activation of the sympathetic nervous system, in a rat model of systolic heart failure. Learning more about the central nervous system mechanisms regulating sympathetic drive in heart failure may help identify novel approaches to the treatment of this devastating disorder.

描述（由申请人提供）：在65岁以上的人中，心力衰竭是美国住院治疗的最常见原因，预计随着人口年龄的增长，该统计数据有望增长。交感神经系统（SNS）的活动过度是心力衰竭综合征的基本表现，也是发病率和死亡率的强有力预测指标。最近的研究表明，大脑中神经化学机制的改变有助于心力衰竭中的SNS活性增强。大脑中有几种兴奋性物质在心力衰竭中出现过多。这些包括血管紧张素II（ANG II），醛固酮（Aldo）和促炎细胞因子（PIC）。这三个动作是为了增加大脑中活性氧的产生，但除此之外，还不清楚它们如何激活SN。我们最近发现，阻止有丝分裂原激活的蛋白激酶（MAPK）的三个主要成分之一，大脑中的细胞内信号传导级联反应大大降低了心力衰竭的大鼠SNS活性。这些MAPK对活性氧的存在敏感，对Ang II，Aldo和PIC的反应，并且在激活时会导致产生更多兴奋性的神经化学物质，这些物质可能有助于持续激活SNS，这是典型的心脏衰竭。该项目的总体目标是确定三个主要的MAPK信号通路在何种程度上有助于在大脑的关键心血管调节中心（下丘脑（PVN）的室内脑血管调节中心，在心脏失败中引起SNS活性。在具有收缩性心力衰竭的大鼠和用Ang II，Aldo和PIC处理的正常大鼠中，我们将确定：1）三个主要MAPK信号通路对PVN中兴奋性介体表达的影响； 2）MAPK信号在PVN中对SNS活性的影响； 3）表达MAPK信号传导的PVN-神经元，小胶质细胞，星形胶质细胞和血管周围巨噬细胞中细胞的表型及其对兴奋性介体产生的影响和交感神经的影响。分子，免疫组织化学和电生理技术的结合将用于阐明脑MAPK信号传导影响SNS活性的机制。我们希望这些研究能够确定用于收缩性心力衰竭治疗干预的新目标。公共卫生相关性：该项目研究了关键细胞内信号传导机制，有丝分裂原激活的蛋白激酶的作用，在兴奋性介质（血管紧张素II，醛固酮II，醛固酮和促炎性细胞因子）中的上调以及随后在相关神经系统中的激活在大脑中的激活，并在styoical Heart the systolic Heart失败中激活。了解有关调节心力衰竭交感神经驱动的中枢神经系统机制的更多信息，可能有助于确定治疗这种毁灭性疾病的新方法。