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：
8589602
负责人：
Robert B Felder
金额：
$ 37万
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 2015-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8589602
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 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的最常见原因那些年龄在65岁以上的人，随着人口年龄的增长，该统计数据将增长。交感神经系统（SNS）的过度活动性是心脏的基本表现失败综合征，以及发病率和死亡率的有力预测指标。最近的研究表明大脑中神经化学机制的改变有助于增强SNS活性心脏衰竭。大脑中有几种兴奋性物质在心脏中过多失败。其中包括血管紧张素II（ANG II），醛固酮（Aldo）和促炎细胞因子（PIC）。这三个动作以增加大脑中活性氧的产生，但是除此之外，还不清楚它们如何激活SNS。我们最近发现阻止有丝分裂原激活蛋白激酶（MAPK）细胞内的三个主要成分之一大脑中的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，并且在激活后，导致产生更多兴奋性神经化学物质这可能有助于SNS的持续激活，这是心力衰竭的典型特征。这该项目的总体目标是确定三个主要MAPK信号在多大程度上途径在关键心血管调节中有助于兴奋性神经化学环境大脑的中心，下丘脑（PVN）的室室核，驱动SNS活性心力衰竭。在具有收缩性心力衰竭的大鼠中，在用Ang II治疗的正常大鼠中，Aldo 和诱导MAPK活动的PIC，我们将确定：1）三个主要MAPK的影响对PVN兴奋性介体表达的信号通路； 2） SNS活动中PVN中的MAPK信号传导； 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信号及其影响兴奋性介体和同情激发的影响。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用于收缩性心力衰竭治疗干预的新颖靶标。