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：
8230514
负责人：
Dorothy Eileen Vatner
金额：
$ 35.84万
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 2013-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8230514
关键词：
1-Phosphatidylinositol 3-Kinase Address Animal Model Cardiac Cardiac Myocytes Cell Survival Clinical Complex Data Family suidae Gene Delivery Gene Expression Profile 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 Phosphotransferases Physiological Pre-Clinical Model Prevention Protein Isoforms Reperfusion Therapy Risk Signal Pathway Signal Transduction Small Interfering RNA Stress System Techniques Transgenic Mice Transgenic Organisms Unstable angina Validation Vascular Endothelial Growth Factors base bone morphogenetic protein receptors conditioning human FRAP1 protein 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）：尽管通过早期再灌注的技术极大地改善了心肌缺血的预后，但预防不可逆的缺血性损害仍然是治疗的关键方面。一种有吸引力的预防心肌缺血的新型治疗途径与心脏前空调的可能性有关，在这种可能发生潜在致命性缺血之前，可以实现生存途径的激活。缺血性预处理代表体内心脏保护的“黄金标准”方法，但在临床环境中仍然很难使用。我们建议H11激酶/Hsp22（H11K）既需要且足以再现基因表达的模式，而基因表达的模式则表征了由缺血性预处理的“延迟”或第二个窗口所赋予的心脏保护图（SWOP）。 H11K是一种主要在心脏中表达的伴侣，在动物模型和患者中，其表达在各种形式的缺血性心脏病中增加。在心脏病模型中，心脏特异性转基因（TG）小鼠中H11K的表达增加足以提供针对与缺血性预处理相似的缺血的保护。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传导途径。我们提出了一种原始途径，其中H11K刺激骨形态发生蛋白（BMP）受体会导致磷脂酰肌醇-3激酶（PI-3K）激活Akt和Rapamycin（MTORC）2（MTORC）2（MMTORC 2（MMTORC）2（MMTORC）2（MMTOR）2（MMTOR）2（MMTORC）2（MM）。第二个目标（假设2：生理相关性）是依靠我们生成的敲除（KO）小鼠模型，以证明H11K对于心脏细胞存活是必要的，尤其是对于延迟预处理的机制。第三个目标（假设3：临床潜力）是确定体内H11K的短期递送是否足以在致死性缺血的情况下促进心脏细胞的存活，这将为验证心脏前先发性条件的概念奠定基础。我们将将体外模型（TG和KO）和一个临床前模型（猪中的基因递送）与小鼠模型相结合，以全面解决这些目标。公共卫生相关性：叙述性叙事尽管心肌缺血的预后通过早期再灌注的技术得到了极大的改善，但预防不可逆的缺血性损害仍然是治疗的关键方面。一种有吸引力的预防心肌缺血的新型治疗途径与心脏空虚调节的可能性有关，其中有缺血性心脏病的患者可能会激活生存途径，这些患者有可能患有随后的致死性缺血的风险。这些患者将包括那些心绞痛，严重和重复性缺血性发作的患者，以及计划进行手术血运重建的患者。在这些情况下，生存信号传导机制的先发性激活将在以下缺血应力期间赋予预防性心脏保护。