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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：
8399052
负责人：
Robert B Felder
金额：
$ 35.94万
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/8399052
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

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. Overactivity 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.

心力衰竭是美国住院治疗的最常见原因， 65岁以上的人，预计这一统计数据将随着人口老龄化而增长。交感神经系统（SNS）的过度活跃是心脏的主要表现衰竭综合征，以及发病率和死亡率的强预测因子。最近的研究表明，大脑中改变的神经化学机制有助于增强SNS活动，心衰几种兴奋性物质出现在大脑中过量在心脏失败这些包括血管紧张素II（ANG II）、醛固酮（ALDO）和促炎因子。细胞因子（PIC）。这三种物质都能增加大脑中活性氧的产生，但除此之外，根本不清楚他们如何激活SNS。我们最近发现，细胞内丝裂原活化蛋白激酶（MAPK）的三种主要成分之一在心力衰竭大鼠中，大脑中的信号级联显著降低了SNS活性。这些 MAPK对活性氧的存在敏感，对ANG II、ALDO和 PIC，并且，当被激活时，导致产生更多的兴奋性神经化学物质这可能导致SNS的持续激活，这是心力衰竭的典型特征。的本项目的总体目标是确定在何种程度上三个主要的MAPK信号转导通路有助于兴奋性神经化学环境中的关键心血管调节大脑的中心，下丘脑室旁核（PVN），驱动SNS活动心脏衰竭在收缩性心力衰竭大鼠和正常大鼠中，ANG II、ALDO 和PIC诱导MAPK活性，我们将确定：1）三种主要MAPK的作用信号通路对室旁核兴奋性介质表达的影响; 2） PVN中MAPK信号传导对SNS活性的影响; 3）PVN -神经元中细胞的表型，小胶质细胞，星形胶质细胞和血管周围巨噬细胞-表达MAPK信号，影响兴奋性介质和交感神经兴奋的产生。的组合分子，免疫组织化学和电生理技术将用于阐明脑MAPK信号传导影响SNS活性的机制。我们希望这些研究将确定收缩性心力衰竭治疗干预的新靶点。