权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Regulation of Cardiac Kv Channel Expression

心脏 Kv 通道表达的调节

基本信息

批准号：
8442902
负责人：
EDWIN S LEVITAN
金额：
$ 36.89万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-12-20 至 2015-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8442902
关键词：
3&apos Untranslated Regions AUF1A protein Address Affect Angiotensin II Animals Apoptosis Arrhythmia Binding Cardiac Cardiac Myocytes Cause of Death Congestive Heart Failure Endocytosis Endosomes Funding Gene Expression Generations Genes Genetic Transcription Heart Heart failure Histology Hormones Human Hypertension Incidence Infusion procedures Knockout Mice Lead MAPK14 gene Mammals Measurement Mechanics Mediating Messenger RNA Molecular NADPH Oxidase Oxidases Pathologic Pathway interactions Phase Phosphotransferases Potassium Channel Proteins Pump RNA Degradation RNA Stability Regulation Reporter Role Signal Pathway Signal Transduction Stretching Sudden Death Superoxides Testing Time Transcriptional Regulation Up-Regulation base calmodulin-dependent protein kinase II constriction follow-up heart function in vivo insight male mitogen-activated protein kinase p38 novel pressure promoter public health relevance research study response superoxide-generating NADPH oxidase therapeutic target

项目摘要

DESCRIPTION (provided by applicant): Heart failure is associated with remodeling of the electrical and mechanical function of the heart. A common feature of electrical remodeling seen under a wide variety of pathologic states in many mammals is decreased expression of transient outward current (Ito) channels, which alters heart function and may contribute to arrhythmias that cause sudden death. Experiments in the current funding period showed that Kv4.3 messenger RNA (mRNA), which limits Ito channel expression in humans, is destabilized in cultured cardiac myocytes by stretch and Angiotensin II (AII), a hormone implicated in hypertension and congestive heart failure. Destabilization is induced by Nadph oxidase (Nox)-generated superoxide and activation of ASK1 and p38 kinase, resulting in induced expression of AUF1, a protein upregulated in human heart failure that can directly bind to a non-canonical sequence in the channel mRNA. Our recent studies show that AII acts via endosomes and CamKII (calmodulin dependent protein kinase II) to induce biphasic activation of p38 kinase. Furthermore, the AUF1 promoter is activated, implicating transcriptional regulation. Finally, preliminary experiments suggest that AUF1 knockout mice are compromised in their response to transverse aortic constriction (TAC), showing that AUF1 is important for the in vivo cardiac response to pressure overload. Here we study the signaling responsible for downregulating Kv4.3 gene expression, because (a) this channel is an evolutionarily conserved target of cardiac electrical remodeling, (b) AUF1 may regulate expression of many genes in the pathologic heart, (c) Nox, CamKII and p38 kinase have been implicated in heart failure and cardiac myocyte apoptosis, and (d) delayed endosome-induced p38 kinase signaling may be a therapeutic target for maintaining cardiac function without arrhythmia during heart failure. Aim 1 will determine the temporal organization of endosome-superoxide signaling in cardiac myocytes. Aim 2 will determine the mechanisms responsible for enhanced expression and function of AUF1. Aim 3 will use knockout mice to elucidate in vivo how AUF1 affects the healthy and pathologic heart. New molecular and cellular mechanisms for controlling cardiac myocyte gene expression will be revealed by these studies.

描述（由申请人提供）：心力衰竭与心脏电功能和机械功能的重塑有关。在许多哺乳动物的各种病理状态下观察到的电重构的共同特征是瞬时外向电流（Ito）通道的表达减少，其改变心脏功能并可能导致导致导致猝死的心律失常。在当前资助期内的实验表明，限制人类Ito通道表达的Kv4.3信使RNA（mRNA）在培养的心肌细胞中因拉伸和血管紧张素II（AII）而不稳定，血管紧张素II是一种与高血压和充血性心力衰竭有关的激素。NADPH氧化酶（Nox）产生的超氧化物和ASK1和p38激酶的激活诱导去稳定，导致诱导表达AUF1，一种在人心力衰竭中上调的蛋白质，可以直接结合到通道mRNA中的非典型序列。我们最近的研究表明，AII通过内体和CamKII（钙调蛋白依赖性蛋白激酶II）诱导p38激酶的双相激活。此外，AUF1启动子被激活，涉及转录调控。最后，初步的实验表明，AUF1敲除小鼠在其响应横向主动脉缩窄（TAC）的妥协，表明AUF1是重要的在体内心脏对压力超负荷的反应。在这里，我们研究了下调Kv4.3基因表达的信号转导，因为（a）该通道是心脏电重构的进化保守靶点，（B）AUF 1可能调节病理心脏中许多基因的表达，（c）Nox、CamK II和p38激酶与心力衰竭和心肌细胞凋亡有关，和（d）延迟的内体诱导的p38激酶信号传导可能是在心力衰竭期间维持心脏功能而无心律失常的治疗靶点。目的1将确定心肌细胞内体超氧化物信号的时间组织。目的2将确定负责增强AUF1的表达和功能的机制。目的3将使用基因敲除小鼠来阐明体内AUF1如何影响健康和病理心脏。这些研究将揭示新的心肌细胞基因表达调控的分子和细胞机制。