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”）是世界上最常见的发病和死亡原因之一。冠状动脉血流的突然停止会在数小时内导致心肌细胞因凋亡和坏死而大量死亡。通过血管成形术/支架置入术进行即时心肌再灌注是目前最佳的治疗方法，但其有效性受到狭窄的治疗时间窗的限制。对低等生物和哺乳动物的研究表明，细胞死亡的很大一部分（包括细胞凋亡和坏死）是以有意且高度调控的方式发生的。这表明心肌梗塞期间的细胞死亡可以通过治疗来控制。 PI 和其他人的大量工作已经描述了心脏细胞死亡的多种机制。重要的是，这项工作表明，心肌梗塞期间的心肌细胞死亡可以被抑制，从而减少梗塞面积并保留心脏功能。我们希望利用化学生物学方法来推动这些发现，以实现以下目标：目标 1. 对小分子进行高通量的基于细胞的初步筛选，这些小分子可调节心肌细胞的死亡，以响应与心肌相关的死亡刺激。梗塞。我们与桑福德-伯纳姆研究所联合开展的初步研究证明了我们的检测已做好准备。目标 2. 在高通量筛选中进一步评估影响细胞死亡的化学物质，以了解其对其他死亡刺激和细胞类型的影响的广泛性以及途径的特异性。将采用更严格和特异性的细胞死亡测定。此外，还将绘制目标路径。目标 3. 使用完整、分离、缓冲液灌注的心脏在心肌梗塞离体模型中测试最终探针及其最佳相关类似物。据我们所知，这是第一个针对心肌梗塞的公正化学筛查。希望所产生的探针将（a）促进未来对细胞凋亡和坏死之间的机制联系的描述，这是一个至关重要的问题； (b) 为未来开发减少梗塞面积并延缓心肌梗塞进展的药物奠定基础。公共卫生相关性：心肌梗塞（“心脏病发作”）是世界上最常见的致残和死亡原因之一。在心肌梗塞期间，大量心肌细胞死亡。该申请旨在识别可用于（a）确定心肌细胞如何死亡和（b）创建减少这种细胞死亡的药物的化学物质。