Pre-emptive conditioning of the ischemic heart

缺血性心脏的先发性调理

基本信息

批准号：
7787538
负责人：
Christophe Depre
金额：
$ 39万
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：
2009
资助国家：
美国
起止时间：
2009-03-16 至 2013-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7787538
关键词：
1-Phosphatidylinositol 3-Kinase Address Animal Model Bone Morphogenetic Proteins Cardiac Cardiac Myocytes Cell Survival Clinical Complex Data Family suidae Gene Delivery Gene Expression Genes Genetic Genetic Transcription Genomics Glucose Goals Gold Heart Heart Diseases In Vitro Infarction Ischemia Ischemic Preconditioning Knock-out Knockout Mice Mediating Methods Modeling Molecular Molecular Chaperones Myocardial Ischemia Nitric Oxide Nitric Oxide Synthase Nuclear Envelope Operative Surgical Procedures PTGS2 gene Pathway interactions Patient Schedules Patients Pattern Phosphotransferases Physiological Pre-Clinical Model Prevention Protein Isoforms Reperfusion Therapy Risk Signal Pathway Signal Transduction Sirolimus Small Interfering RNA Stress System Techniques Transgenic Mice Transgenic Organisms Unstable angina Validation Vascular Endothelial Growth Factors base bone morphogenetic protein receptors conditioning improved in vivo mTOR protein mouse model multicatalytic endopeptidase complex novel therapeutics outcome forecast preconditioning prophylactic public health relevance response transcription factor valosin-containing protein

项目摘要

DESCRIPTION (provided by applicant): Although the prognosis of myocardial ischemia has been dramatically improved by the techniques of early reperfusion, the prevention of irreversible ischemic damage remains a critical aspect of the treatment. An appealing novel therapeutic avenue for the prevention of myocardial ischemia relates to the possibility of a pre- emptive conditioning of the heart, in which an activation of survival pathways could be achieved before potentially lethal ischemia occurs. Ischemic preconditioning represents the "gold standard" method of cardioprotection in vivo but it remains difficult to use in the clinical setting. We propose that H11 kinase/Hsp22 (H11K) is both necessary and sufficient to reproduce the pattern of gene expression that characterizes the cardioprotection conferred by the "delayed" or second window of ischemic preconditioning (SWOP). H11K is a chaperone expressed predominantly in the heart, the expression of which increases in various forms of ischemic heart disease, both in animal models and in patients. Increased expression of H11K in a cardiac- specific transgenic (TG) mouse to a level comparable to that found in models of heart disease is sufficient to provide protection against ischemia that is quantitatively similar to ischemic preconditioning. Based on the Preliminary Data, we have three goals. The first goal (Hypothesis 1: Molecular Mechanisms) is to better define the signaling pathway by which H11K promotes cardiac survival. We propose an original pathway in which the stimulation of the bone morphogenetic protein (BMP) receptor by H11K results in the activation of phosphatidylinositol-3 kinase (PI-3K) and the subsequent activation of the transcription factor NF-:B by Akt and the mammalian target of rapamycin (mTOR) complex 2 (mTORC2). The second goal (Hypothesis 2: Physiological Relevance) is to rely on a knockout (KO) mouse model that we generated to prove that H11K is necessary for cardiac cell survival, and especially for the mechanisms of delayed preconditioning. The third goal (Hypothesis 3: Clinical Potential) is to determine whether short-term delivery of H11K in vivo is sufficient to promote cardiac cell survival in a context of lethal ischemia, which would lay the basis for validation of the concept of cardiac pre-emptive conditioning. We will combine an in vitro system (isolated cardiac myocytes and gene knockdown) with mouse models in vivo (TG and KO) and a pre-clinical model (gene delivery in the swine) to address these goals comprehensively. PUBLIC HEALTH RELEVANCE: PROJECT NARRATIVE Although the prognosis of myocardial ischemia has been dramatically improved by the techniques of early reperfusion, the prevention of irreversible ischemic damage remains a critical aspect of the treatment. An appealing novel therapeutic avenue for the prevention of myocardial ischemia relates to the possibility of a pre- emptive conditioning of the heart, in which an activation of survival pathways could be achieved in patients with ischemic heart disease who are at risk for a subsequent lethal ischemia. These patients would include those with unstable angina, or with severe and repetitive ischemic episodes, and patients scheduled for surgical revascularization. In these situations, the pre-emptive activation of survival signaling mechanisms would confer a prophylactic cardioprotection during the following ischemic stress.

描述（由申请人提供）：虽然心肌缺血的预后已通过早期再灌注技术显着改善，但预防不可逆的缺血性损伤仍然是治疗的关键方面。预防心肌缺血的一种有吸引力的新颖治疗途径涉及先发制人的心脏调节的可能性，其中可以在潜在的致命性缺血发生之前激活生存途径。缺血预处理代表了体内心脏保护的“金标准”方法，但在临床环境中仍然难以使用。我们认为，H11 激酶/Hsp22 (H11K) 对于重现基因表达模式来说既是必要的又是充分的，该模式表征了“延迟”或第二个缺血预适应窗口 (SWOP) 所赋予的心脏保护作用。 H11K 是一种主要在心脏中表达的伴侣蛋白，其表达在各种形式的缺血性心脏病（无论是在动物模型还是在患者中）中都会增加。将心脏特异性转基因 (TG) 小鼠中 H11K 的表达增加至与心脏病模型中发现的水平相当的水平，足以提供与缺血预处理在数量上相似的缺血保护。根据初步数据，我们有三个目标。第一个目标（假设 1：分子机制）是更好地定义 H11K 促进心脏存活的信号通路。我们提出了一种原始途径，其中 H11K 刺激骨形态发生蛋白 (BMP) 受体导致磷脂酰肌醇-3 激酶 (PI-3K) 激活，随后 Akt 和 NF-:B 激活转录因子 NF-:B哺乳动物雷帕霉素靶标 (mTOR) 复合物 2 (mTORC2)。第二个目标（假设 2：生理相关性）是依靠我们生成的基因敲除 (KO) 小鼠模型来证明 H11K 对于心脏细胞存活是必需的，尤其是延迟预处理的机制。第三个目标（假设3：临床潜力）是确定体内短期递送H11K是否足以促进致死性缺血情况下心肌细胞的存活，这将为验证心脏预缺血概念奠定基础。空性调节。我们将把体外系统（分离的心肌细胞和基因敲低）与体内小鼠模型（TG 和 KO）以及临床前模型（猪体内的基因传递）相结合，以全面实现这些目标。公众健康相关性：项目叙述尽管早期再灌注技术已显着改善心肌缺血的预后，但预防不可逆的缺血性损伤仍然是治疗的一个关键方面。预防心肌缺血的一种引人注目的新颖治疗途径涉及先发制人的心脏调节的可能性，其中可以激活有随后发生致命性缺血风险的缺血性心脏病患者的生存途径。这些患者包括患有不稳定心绞痛或严重且反复缺血发作的患者，以及计划进行血运重建手术的患者。在这些情况下，生存信号机制的先发制人激活将在随后的缺血应激期间提供预防性心脏保护。