Role of H11 kinase in cardiac cell growth

H11 激酶在心肌细胞生长中的作用

基本信息

批准号：
7150612
负责人：
Christophe Depre
金额：
$ 36.86万
依托单位：
UNIV OF MED/DENT OF NJ-NJ MEDICAL SCHOOL
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-12-01 至 2007-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7150612
关键词：
Address Adenoviruses Affect Agreement Apoptosis Canis familiaris Cardiac Cardiac Myocytes Cell Death Cell Proliferation Cell Survival Cells Chronic Condition Data Doctor of Philosophy Dominant-Negative Mutation Family suidae Gene Expression Genes Goals Growth Growth and Development function HSPB1 gene Heart Heart Hypertrophy Heart failure Heat shock proteins Herpes Simplex Infections Homologous Gene Hypertrophy In Vitro Injury Ischemia Knock-out Left Ventricular Hypertrophy Life Mediating Mitotic Modeling Mus Muscle Cells Myocardial Ischemia Myocardium Normal tissue morphology Nuclear Nucleosomes Pathway interactions Pattern Phenotype Phosphotransferases Physiological Physiological reperfusion Protein Kinase Protein Overexpression Proteins Regulation Reperfusion Therapy Reporting Role Signal Pathway Signal Transduction Simulate Skeletal Muscle Specificity Testing Tissues Transcript Transgenic Mice Transgenic Model Transgenic Organisms Up-Regulation Viral Virus Yeasts base cDNA Arrays cancer cell casein kinase II cell growth cell injury cell transformation functional genomics in vivo malignant breast neoplasm melanoma mouse model mutant novel novel therapeutics nucleosome assembly protein I protein activation ras GTPase-Activating Proteins research study response tumor ventricular hypertrophy yeast two hybrid system

项目摘要

DESCRIPTION (provided by applicant): H11 kinase is the eukaryotic homologue of ICP10 protein kinase, a Ras-GAP kinase from Herpes Simplex required for virus growth. In normal tissues, H11 kinase expression is restricted to the heart and skeletal muscle. Although its function remains unknown, H11 kinase probably participates in mechanisms of cell growth because its induction in non-muscular cells promotes transformation into cancer cells. Putative interactions include the nuclear casein kinase II (NUCKS II), a stimulator of cell growth, the protein HSP27, a stimulator of cell survival, and the nucleosome assembly protein-1 (NAP-l), a stimulator of cell proliferation. By subtractive hybridization, we unexpectedly found that H11 kinase transcript and protein are upregulated in large mammalian models of reversible ischemia/reperfusion and chronic left ventricular hypertrophy. Our preliminary data show that overexpression of H11 kinase in isolated cardiac myocytes promotes cell growth. A cardiac-specific transgenic mouse has been generated, which confirms that overexpression of H11 kinase induces cardiac hypertrophy and protects against cell death during ischemia/reperfusion in vivo. Based on these observations, the overall goal of this proposal is to determine the physiological role, signaling mechanisms and functional importance of H11 kinase in the myocardium. The first specific aim is to determine in vivo the functional and genomic effects of H11 kinase overexpression in a cardiac-specific transgenic mouse model submitted to transverse aortic banding or ischemia/reperfusion. We hypothesize that H11 kinase overexpression in transgenic mice will decrease irreversible cellular damage in hypertrophied and ischemic hearts. The second aim is to determine the signaling pathways in which H11 kinase is integrated. We hypothesize that H11 kinase promotes cardiac growth and survival by stimulating NUCKS II, HSP27 and NAP-l, but that other unexpected proteins might interact as well. The third aim is to show, both in vitro with a dominant negative and in vivo in a knock-out model, that H11 kinase represents an essential pathway of cardiac growth and survival. We hypothesize that the tissue-restricted expression of H11 kinase underlies a specific signaling pathway that is not dispensable for normal cardiac cell growth. These experiments will unravel novel mechanisms and signaling pathways of cardiac growth, which may result in new therapeutic avenues for both ischemic heart disease and heart failure.

描述（由申请人提供）：H11激酶是ICP10蛋白激酶的真核同源物，ICP10蛋白激酶是病毒生长所需的单纯疱疹的Ras-gap激酶。在正常组织中，H11激酶表达仅限于心脏和骨骼肌。尽管其功能仍然未知，但H11激酶可能参与细胞生长的机制，因为它在非肌肉细胞中诱导会促进转化为癌细胞。推定的相互作用包括核酪蛋白激酶II（Nucks II），一种细胞生长的刺激剂，蛋白质HSP27，细胞存活的刺激剂和核小体组装蛋白-1（NAP-L），一种细胞增殖的刺激剂。通过减法杂交，我们出乎意料地发现，在可逆性缺血/再灌注和慢性左心室肥大的大型哺乳动物模型中，H11激酶转录和蛋白质上调。我们的初步数据表明，孤立心肌细胞中H11激酶的过表达可促进细胞生长。已经产生了一种心脏特异性的转基因小鼠，它证实了H11激酶的过表达会诱导心脏肥大，并在体内缺血/再灌注期间预防细胞死亡。基于这些观察结果，该提案的总体目标是确定H11激酶在心肌中的生理作用，信号传导机制和功能重要性。第一个具体目的是在体内确定H11激酶过表达的功能和基因组效应，在提交给横向主动脉谱带或缺血/再灌注的心脏特异性转基因小鼠模型中。我们假设转基因小鼠中的H11激酶过表达将减少肥厚和缺血性心脏中不可逆的细胞损伤。第二个目的是确定H11激酶积分的信号传导途径。我们假设H11激酶通过刺激Nucks II，HSP27和NAP-L促进心脏生长和存活，但是其他意外蛋白也可能相互作用。第三个目的是在敲除模型中表现出具有显性阴性和体内的体外体外表现，H11激酶代表了心脏生长和生存的必要途径。我们假设H11激酶的组织限制表达是一种特定的信号传导途径，该信号通路对于正常的心脏细胞生长而言不足。这些实验将揭开心脏生长的新机制和信号传导途径，这可能导致缺血性心脏病和心力衰竭的新治疗途径。