Cell Death Promoting Mechanisms of Mst1

Mst1促进细胞死亡的机制

基本信息

批准号：
7907574
负责人：
Junichi Sadoshima
金额：
$ 33.91万
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：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/7907574
关键词：
Address Apoptosis Apoptotic Cardiac Cardiac Myocytes Cardiotoxicity Cell Death Cell physiology Cessation of life Complement component C1s Congestive Heart Failure Development Doctor of Philosophy Down-Regulation Doxorubicin Endoplasmic Reticulum Feedback Functional disorder Funding Gene Expression Genes Genetic Transcription Goals Heart Heart failure Hypertrophy In Vitro Infarction Ischemia Knowledge MAP3K1 gene Mediating Methods Mitochondria Mitochondrial Proteins Modality Molecular Myocardial Infarction Myocardial Ischemia Nuclear Pathologic Pathway interactions Patients Phosphorylation Phosphotransferases Play Principal Investigator Protein Kinase Reperfusion Therapy Research Design Role Signal Pathway Signal Transduction Sterility Stimulus Stress Transgenic Mice biological adaptation to stress endoplasmic reticulum stress mouse model novel prevent response

Address Apoptosis Apoptotic Cardiac Cardiac Myocytes Cardiotoxicity Cell Death Cell physiology Cessation of life Complement component C1s Congestive Heart Failure Development Doctor of Philosophy Down-Regulation Doxorubicin Endoplasmic Reticulum Feedback Functional disorder Funding Gene Expression Genes Genetic Transcription Goals Heart Heart failure Hypertrophy In Vitro Infarction Ischemia Knowledge MAP3K1 gene Mediating Methods Mitochondria Mitochondrial Proteins Modality Molecular Myocardial Infarction Myocardial Ischemia Nuclear Pathologic Pathway interactions Patients Phosphorylation Phosphotransferases Play Principal Investigator Protein Kinase Reperfusion Therapy Research Design Role Signal Pathway Signal Transduction Sterility Stimulus Stress Transgenic Mice biological adaptation to stress endoplasmic reticulum stress mouse model novel prevent response

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项目摘要

We have shown previously that a positive feedback (amplification) mechanism between the stress responsive protein kinases, including mammalian sterile 20 like kinase 1 (Mst1), and the cell death promoting mechanisms is critical in mediating cardiac myocyte apoptosis. In particular, activation of Mst1 plays a critical role in mediating cardiac myocyte apoptosis in response to ischemia/reperfusion (I/R). Mst1 also plays an important role in mediating cardiac dysfunction during cardiac remodeling after myocardial infarction (Ml). Detailed analyses regarding the cellular function of Mst1 have suggested that the proapoptoic kinase Mst1 not only mediates cardiac myocyte apoptosis but also initiates multiple other cellular effects, such as inhibition of compensatory hypertrophy and downregulation of mitochondrial gene expression, intimately contributing to the development of cardiac dysfunction. Our analyses regarding the downstream targets of Mst1 have suggested that 1) an evolutionary conserved signaling pathway consisting of hWW45 and Lats2 mediates the proapoptotic effects of Mst1; 2) Mst1 phosphorylates PERK, an endoplasmic reticulum (ER) kinase, thereby initiating ER stress responses; 3) Mstl downregulates expression of mitochondrial genes through downregulation and transcriptional inactivation of PGC-1 alpha. Our goals are to further demonstrate the importance of these Mst1 targets in mediating heart failure in response to I/R and during cardiac remodeling. We hypothesize that: A. hWW45-Lats2 mediates the proapoptotic function of Mst1. B. Mst1 activates PERK, thereby mimicking ER stress in the heart. C. Mst1 phosphorylates PGC-1 alpha, thereby inhibiting expression of nuclear encoded mitochondrial genes. We will address these issues using newly developed transgenic mouse models as well as in vitro studies designed to determine the underlying molecular mechanisms. Our study will establish the novel linkage between the pro-apoptotic signaling mechanism and the downstream mechanisms leading to cardiac dysfunction. Knowledge obtained from this study should be useful for the development of novel modalities for treatment of ischemic heart diseases and congestive heart failure.

我们先前已经表明，应力之间的正反馈（放大）机制反应性蛋白激酶，包括哺乳动物无菌20，如激酶1（MST1）和细胞死亡促进机制对于介导心肌细胞凋亡至关重要。特别是激活MST1 响应缺血/再灌注（I/R）介导心肌细胞凋亡（I/R）中起着至关重要的作用。 MST1 心肌后心脏重塑期间介导心脏功能障碍也起着重要作用梗塞（ML）。有关MST1的细胞功能的详细分析表明，propoptoic 激酶MST1不仅介导心肌细胞凋亡，而且还引发了多个其他细胞效果，例如抑制补偿性肥大和线粒体基因的下调表达，密切有助于心脏功能障碍的发展。我们关于 MST1的下游靶标表明1）一个进化保守的信号通路 HWW45和LATS2介导MST1的促凋亡作用； 2）MST1磷酸化PERK，A 内质网（ER）激酶，从而启动ER应力反应； 3）MSTL下调通过下调和PGC-1α的转录失活的线粒体基因的表达。我们的目标是进一步证明这些MST1目标在调解心力衰竭中的重要性对I/R的响应以及心脏重塑期间。我们假设：A。HWW45-LATS2介导促凋亡 MST1的功能。 B. MST1激活PERK，从而模仿心脏中的ER应力。 C. MST1 磷酸化PGC-1α，从而抑制核编码线粒体基因的表达。我们将使用新开发的转基因小鼠模型以及设计的研究确定潜在的分子机制。我们的研究将建立新的联系促凋亡信号传导机制和导致心脏功能障碍的下游机制。从这项研究中获得的知识对于开发用于治疗的新型方式应该很有用缺血性心脏病和充血性心力衰竭。