Conditional HSF1 Expression for Ischemic Cardioprotection

条件性 HSF1 表达对缺血性心脏保护作用

• 批准号: 7689421
• 负责人: Ivor James Benjamin
• 金额: --
• 依托单位: VA SALT LAKE CITY HEALTHCARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-01 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7689421
• 关键词: Accounting; Acute; Acute myocardial infarction; Address; Adjuvant Therapy; Affect; Angiotensin-Converting Enzyme Inhibitors; Animal Model; Apoptosis; Arrhythmia; Arteries; Biochemical; Biological; Blood Platelets; Blood flow; Calcium; Cardiac; Cardiotonic Agents; Cell Death; Cessation of life; Chronic; Cigarette; Clinic; Clinical; Clinical Research; Clinical Trials; Coronary Artery Bypass; Coronary Occlusions; Cytosol; Endoplasmic Reticulum; Epidemic; Etiology; Event; Free Radical Scavengers; Free Radicals; Functional disorder; Gene Expression; General Population; Genes; Goals; HSF1; Health; Heart; Heart Diseases; Heart Transplantation; Heart failure; Heat shock proteins; Heat-Shock Response; High Prevalence; Homeostasis; Inflammation; Inherited; Injury; Intervention; Ischemia; Knowledge; Laboratories; Left; Left Ventricular Dysfunction; Left Ventricular Ejection Fraction; Left Ventricular Remodeling; Measures; Mediating; Medical; Membrane Lipids; Mitochondria; Modeling; Molecular; Molecular Chaperones; Morbidity - disease rate; Multigene Family; Mus; Myocardial; Myocardial Infarction; Myocardial Ischemia; Myocardial dysfunction; Necrosis; Obesity; Operative Surgical Procedures; Organ; Organelles; Organism; Outcome; Outcome Measure; Oxygen Consumption; Pathway interactions; Patients; Permeability; Population; Prevention; Process; Production; Protein Biosynthesis; Protein Overexpression; Proteins; Randomized; Reactive Oxygen Species; Recovery; Recurrence; Regulatory Pathway; Repression; Research; Research Proposals; Respiration; Sample Size; Sodium; Stimulus; Stress; Stroke; Syndrome; Testing; Therapeutic; Therapeutic Intervention; Time; Tissue-Specific Gene Expression; Tissues; Toxic effect; Trans-Activators; Transgenic Mice; Transgenic Organisms; Treatment Efficacy; United States; Up-Regulation; Ventricular; Ventricular Remodeling; Veterans; Woman; biological adaptation to stress; clinically relevant; cost; design; disorder prevention; efficacy testing; heart metabolism; heat shock transcription factor; heat-shock factor 1; high risk; improved; in vivo; internal control; member; men; mitochondrial dysfunction; mortality; mouse model; nitrosative stress; novel; novel strategies; percutaneous coronary intervention; preclinical study; prevent; programs; protein aggregation; protein expression; protein misfolding; response; restoration; sex; stress protein; sudden cardiac death; thrombolysis

DESCRIPTION (provided by applicant): Different members of the HSP multigene family have been implicated the inhibition of ischemia- induced protein damage, abrogation of protein misfolding/aggregation, and prevention of mitochondrial dysfunction. However, the precise cellular mechanisms remain partially understood and effective strategies for their coordinated recruitment are poorly defined. Robust upregulation of HSP synthesis requires repression of tight basal repression (control) and full activation of the Heat Shock Factor 1 (HSF1) by a highly conserved process triggered by diverse stimuli under stressful conditions. In Preliminary Studies, we have developed a transgenic mouse model carrying a constitutively active HSF1 (caHSF1) transactivator that conveniently circumvents these stress-inducible requirements and provides us the robust versatility to up-regulate global HSP expression in the intact heart. The main objectives of this research application are to definitively address the cellular mechanisms that up-regulation of HSPs by caHSF1 decreases post-ischemic LV dysfunction and improves myocardial salvage. Specifically, we wish to characterize if HSF1-dependent modulation of the cytosolic/unfolded protein response (cyUPR) prevents mitochondrial dysfunction and improves post-ischemic cardiac metabolism. The specific hypothesis, to be tested, is that tissue-specific constitutively active heat shock factor 1 (caHSF1) expression represents a novel chaperone-dependent pathway for preserving mitochondrial permeability transition and cellular protection. The following three specific aims are designed to test this hypothesis: Aim 1: Determine the precise levels of tissue-specific HSP expression required to decrease protein aggregation and to achieve ischemic protection after moderate to severe ischemic challenges ex vivo. Aim 2: Characterize the tissue-specific HSP overexpression for changes in cardiac metabolism and myocardial oxygen consumption under basal and ischemic conditions ex vivo. This aim will address if the chaperone-dependent effects of HSPs directly affects mitochondrial respiration and energy production. Aim 3: Characterize the cellular mechanisms by which conditional HSP overexpression prevents mitochondrial permeability transition (MPT) opening. Conditional strategies are ideally suited for testing the efficacy of interventions to aforementioned clinical outcomes (e.g., myocardial infarction, cardiac arrhythmias, contractile dysfunction). In this proposal, our preclinical studies will address several timely and novel questions related to the elapsed times needed to establish the biological plausibility for therapeutic intervention at the functional, biochemical, molecular and cellular levels. Accordingly, we propose that a conditional caHSF1 animal model permits more rigorous assessment of the mechanisms of ischemic protection on a time scale between intervention and clinical outcomes. Given the burgeoning epidemic of ischemia-related heart failure, there is increased urgency to establish proof-of-principle novel strategies whose administration at the time of acute myocardial infarction might reduce post-ischemic left ventricular dysfunction and favorably improve long-term outcomes, such as heart failure and cardiac sudden death. PUBLIC HEALTH RELEVANCE: 7. Potential Impact on Veterans' Health Heart attacks and strokes account for the first and third leading causes of mortality and morbidity in the United States, respectively. Heart failure from either inherited or acquired conditions claims 500,000 lives annually and costs ~$30 billion dollars in the US alone. Ischemic heart disease-the most common acquired heart disease in both men and women- has a higher prevalence in veterans of both sexes due to higher rates of obesity and cigarette use than the general population. This research proposal seeks to understand the mechanisms of cellular protection with the ultimate goal for disease prevention in the high-risk veteran population. If successful, such beneficial outcomes may improve the health of veterans with acute ischemic syndromes during cardiac transplantation, coronary bypass surgery, and other acquired cardiac conditions.

描述（由申请人提供）： HSP多基因家族的不同成员已被暗示抑制缺血诱导的蛋白质损伤，废除蛋白质错误折叠/聚集以及预防线粒体功能障碍。但是，精确的细胞机制仍然被部分理解，其协调招募的有效策略的定义很差。 HSP合成的强大上调需要通过在压力条件下由多种刺激触发的高度保守的过程来抑制紧密的基础抑制（对照）和热休克因子1（HSF1）的完全激活。在初步研究中，我们开发了一种携带组成型活性HSF1（CAHSF1）的转基因小鼠模型，该模型可方便地避免这些应激诱导的要求，并为我们提供了在完整心脏中上调全局HSP表达的强大多功能性。该研究应用程序的主要目标是确定解决细胞机制，即CAHSF1上调HSP会降低缺血后LV功能障碍并改善心肌挽救。具体而言，我们希望表征胞质/展开蛋白质反应（CYUPR）的HSF1依赖性调节是否可以防止线粒体功能障碍并改善缺血后心脏代谢。要测试的特定假设是组织特异性的组成性热休克因子1（CAHSF1）表达代表了一种新型的伴侣依赖性途径，用于保留线粒体通透性跃迁和细胞保护。以下三个特定目的旨在检验以下假设：目标1：确定减少蛋白质聚集所需的组织特异性HSP表达水平，并在体内中度至重度缺血性挑战后实​​现缺血性保护。 AIM 2：表征组织特异性的HSP过表达，用于在基础和缺血性条件下在体内变化心脏代谢和心肌氧的变化。如果HSP的伴侣依赖性影响直接影响线粒体呼吸和能量产生，则该目标将解决。 AIM 3：表征条件HSP过表达的细胞机制可防止线粒体通透性转变（MPT）开放。有条件的策略非常适合测试上述临床结果的干预措施的功效（例如，心肌梗塞，心律不齐，收缩功能障碍）。在此提案中，我们的临床前研究将解决与在功能，生化，分子和细胞水平上建立生物学合理性所需时间相关的新的新问题。因此，我们建议有条件的CAHSF1动物模型允许在干预和临床结果之间的时间范围内对缺血性保护的机制进行更严格的评估。鉴于与缺血相关心力衰竭的蓬勃发展的流行，建立原理证明的新型策略的紧迫性增加了，在急性心肌梗死时的给药可能会降低缺血后左心室功能障碍，并有利地改善长期的外观，例如心力衰竭和心脏突然死亡。 公共卫生相关性： 7.对退伍军人健康心脏病发作和中风的潜在影响分别解释了美国死亡率和发病率的第一和第三主要原因。从继承或获得的条件中发生的心力衰竭每年索赔50万人的生活，仅在美国，就有约3000亿美元的费用。缺血性心脏病 - 男性和女性最常见的心脏病 - 由于肥胖和吸烟率高于一般人群，因此男女退伍军人的患病率更高。这项研究建议旨在了解细胞保护的机制，并在高危退伍军人人群中预防疾病的最终目标。如果成功的话，这种有益的结果可能会改善心脏移植，冠状动脉搭桥手术和其他获得的心脏状况的急性缺血综合症的退伍军人的健康。