High-Throughput Screen for Small Molecules that Modulate Myocardial Damage

调节心肌损伤的小分子的高通量筛选

基本信息

批准号：
8208101
负责人：
Richard N Kitsis
金额：
$ 4.15万
依托单位：
ALBERT EINSTEIN COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-01-01 至 2012-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8208101
关键词：
Acute Affect Angioplasty Apoptosis Apoptosis Inhibitor Apoptotic Arterial Fatty Streak Biochemical Biological Assay Biological Availability Biology Blood flow Buffers Cardiac Cardiac Myocytes Cell Culture Techniques Cell Death Cell Line Cell model Cells Cessation of life Chemicals Collaborations Coronary Coronary artery Deoxyglucose Dose Drug Kinetics Effectiveness Funding Future Genetic Glucose Glycolysis Heart Hour Hydrogen Infarction Institutes Ischemia Lead Life Link Lower Organism Luciferases Mammals Maps Mediating Medicine Metabolic stress Modeling Molecular Morbidity - disease rate Mus Muscle Cells Myocardial Myocardial Infarction Myocardial Reperfusion Necrosis Oxidative Stress Pathway interactions Pharmaceutical Preparations Proliferating Rattus Readiness Reperfusion Therapy Rupture Screening procedure Simulate Specificity Stimulus Testing Therapeutic Time United States United States National Institutes of Health Viral Tumor Antigens Work analog base cell type clinically relevant college disability drug development fetal heart preservation high throughput screening human IFITM1 protein in vivo mortality myocardial infarct sizing novel programs public health relevance response small molecule

项目摘要

DESCRIPTION (provided by applicant): Myocardial infarction ("heart attack") is one of the most common causes of morbidity and mortality in the world. The sudden cessation of coronary blood flow leads within hours to massive death of heart muscle cells by apoptosis and necrosis. Prompt myocardial reperfusion via angioplasty/stenting is currently the optimal treatment, but its effectiveness is limited by a narrow therapeutic time window. Work in lower organisms and mammals has demonstrated that a significant portion of cell death - both apoptosis and necrosis - occurs in a deliberate and highly regulated manner. This suggests that cell death during myocardial infarction can be therapeutically manipulated. Extensive work from the PI and others has delineated multiple mechanisms of cell death in the heart. Importantly, this work has shown that heart muscle cell death during myocardial infarction can be inhibited resulting in the reduction of infarct size and preservation of cardiac function. We wish to move these discoveries forward using a chemical biology approach through the following aims: Aim 1. To perform a high-throughput cell-based primary screen for small molecules that modulate the death of heart muscle cells in response to death stimuli relevant to myocardial infarction. Our preliminary studies, developed in conjunction with the Sanford-Burnham Institute, demonstrate the readiness of our assay. Aim 2. To further evaluate chemicals that influenced cell death in the high-throughput screen for broadness of effect against other death stimuli and cell types, and for pathway specificity. More stringent and specific cell death assays will be employed. In addition, targeted pathways will be mapped. Aim 3. To test final probe(s) and their best related analogs in an ex vivo model of myocardial infarction using intact, isolated, buffer-perfused hearts. To our knowledge, this is the first unbiased chemical screen directed at myocardial infarction. It is hoped that the probes generated will both (a) facilitate the future delineation of mechanistic linkages connecting apoptosis and necrosis, an issue of fundamental importance; and (b) provide the basis for the future development of drugs that reduce infarct size and retard its progression during myocardial infarction. PUBLIC HEALTH RELEVANCE: Myocardial infarction ("heart attack") is one of the most common causes of disability and death in the world. During myocardial infarction, large numbers of heart muscle cells die. This application proposes to identify chemicals that can be used (a) to determine how heart muscle cells die and (b) to create a medication that reduces this cell death.

描述（由申请人提供）：心肌梗塞（“心脏病发作”）是世界上发病和死亡率最常见的原因之一。冠状动脉血流的突然停止在数小时内导致凋亡和坏死导致心脏肌肉细胞的死亡。目前，通过血管成形术/支架进行迅速的心肌再灌注是最佳治疗方法，但其有效性受到狭窄的治疗时间窗口的限制。在较低的生物体和哺乳动物中的工作表明，细胞死亡的很大一部分（凋亡和坏死）都以故意且高度调节的方式发生。这表明可以操纵心肌梗塞期间的细胞死亡。 PI和其他人的大量工作描述了心脏中细胞死亡的多种机制。重要的是，这项工作表明，心肌梗死过程中的心肌细胞死亡可以抑制，从而导致梗塞大小的减小和心脏功能保留。我们希望通过以下目的使用化学生物学方法向前发展这些发现：目的1。对小分子进行高通量细胞的主要筛选，该筛网对与心肌梗死相关的死亡刺激来调节心脏肌肉细胞的死亡。我们与桑福德·伯纳姆研究所（Sanford-Burnham Institute）共同发展的初步研究证明了我们的测定法。目的2。进一步评估在高通量筛选中影响细胞死亡的化学物质，以实现对其他死亡刺激和细胞类型的效果广泛，以及途径特异性。将采用更严格和具体的细胞死亡测定法。另外，将映射目标途径。 AIM 3。使用完整的，孤立的，缓冲的心脏来测试心肌梗死的离体模型中的最佳相关类似物。据我们所知，这是第一个针对心肌梗塞的无偏化化学筛选。希望产生的探针能够（a）促进将凋亡和坏死连接的机械联系的未来描述，这是一个基本重要性的问题；（b）为降低梗塞大小并在心肌梗塞期间延迟其进展的药物的未来开发提供了基础。公共卫生相关性：心肌梗塞（“心脏病”）是世界上残疾和死亡的最常见原因之一。在心肌梗塞期间，大量心肌细胞死亡。该应用建议识别可以使用的化学物质（a）来确定心肌细胞如何死亡，以及（b）创建减少该细胞死亡的药物。