Protection of Ischemic Myocardium

保护缺血心肌

• 批准号: 8688304
• 负责人: Roberto Bolli
• 金额: $ 250.98万
• 依托单位: UNIVERSITY OF LOUISVILLE
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-04-15 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8688304
• 关键词: Acute; Address; Adrenergic Agents; Affect; Aftercare; Apoptotic; Biology; Carbon Monoxide; Cardiac; Cell Culture Techniques; Cell Proliferation; Cell Separation; Cell Survival; Cell Therapy; Cell Transplantation; Cell Transplants; Cell physiology; Cells; Cellular biology; Cessation of life; Clinical Research; Clinical Trials; Collaborations; Competence; Cytoprotection; Diabetes Mellitus; Effectiveness; Engraftment; Environment; Flow Cytometry; Funding; Gases; Goals; Heart; Heart failure; Human; Hypoxia; Infarction; Inflammatory; Instruction; Insulin Resistance; Investigation; Ischemia; Knowledge; Lead; Left Ventricular Remodeling; Length; Manuscripts; Mediating; Molecular; Motivation; Mus; Muscle Cells; Myocardial; Myocardial Infarction; Myocardial Ischemia; Myocardium; Natural regeneration; Nitric Oxide; Non-Insulin-Dependent Diabetes Mellitus; Operative Surgical Procedures; Outcome; Pathology; Patients; Phenotype; Play; Positioning Attribute; Progress Reports; Property; Proteins; Proto-Oncogene Protein c-kit; Recording of previous events; Regulation; Reperfusion Injury; Research Infrastructure; Research Personnel; Resistance; Role; Signal Pathway; Signal Transduction; Stem cells; Stress; TNF gene; TNFRSF1A gene; TNFRSF1B gene; Testing; Therapeutic; Therapeutic Uses; Tissues; Translating; Translations; Transplantation; Treatment Efficacy; Work; abstracting; adrenergic; base; cardiac repair; cytokine; diabetic; experience; improved; insight; paracrine; programs; repaired; response; stem

Lack of understanding of basic stem cell mechanisms limits current therapeutic approaches. In this renewal application, we will focus on the use of c-kit* cardiac progenitor cells (CPCs) to protect the heart against post-myocardial infarction (Ml) remodeling and heart failure (HF). The overall goal is to elucidate the molecular mechanisms that regulate the properties of CPCs and to evaluate the therapeutic utility of enhancing CPC function in order to optimize cardiac repair. Four closely inter-related and inter-dependent Projects will address different facets of this theme. Project 1 (Belli) will elucidate the role of CO and NO in regulating CPC function and therapeutic efficacy. The central hypothesis is that these gases are kev determinants of CPC competence and that augmenting their levels will dramatically enhance CPC-mediated cardiac repair. Project 2 (Prabhu) will illuminate the deleterious effects of TNF on CPC competence and reparative ability. This project will test the hypothesis that differential TNF signaling via TNFR1, TNFR2, and NF-KB plavs a critical role in determining adrenergic versus cardiomyogenic fate and, consequently, the reparative capacity of CPCs following Ml. Project 3 (Jones) will examine the role of protein 0-GlcNAcylation in modulating the fundamental properties of CPCs and will test the hypothesis that the 0-GlcNAc alarm signal plays a critical role in regulating CPC proliferation, survival, differentiation, and paracrine function. Project 4 (Bhatnagar) will determine how diabetes affects CPC-mediated myocardial repair and how CPC therapy can be optimized for the diabetic heart. The central hypothesis is that diabetes undermines CPC competence by inducing insulin resistance. Thus, all four Projects focus cohesively on CPCs. These Projects will be supported by four Cores that will provide expertise in mouse surgery, cell transplantation, CPC culture and phenotyping, pathology, flow cytometry, and cell sorting. This highly-focused PPG will be led by investigators who have collaborated productively for many years. Their long history of collaboration has resulted in closely integrated Projects that are ideally suited for a PPG. These will be the first studies to examine the role of CO and NO, TNF, 0-GlcNAcylation, and type 2 diabetes on CPC function: consequently, the results will be entirely new and will advance our understanding of CPC biology. In addition, these studies may lay the groundwork for new translational investigations of CPC therapy in patients with HF. Since we have already initiated the first-in-humans clinical trial of unmodified CPCs in patients with HF, we are well positioned to rapidly translate any insights derived from this Program into new clinical investigations.

对基本干细胞机制的缺乏了解限制了当前的治疗方法。在此续签应用中，我们将重点介绍使用C-KIT*心脏祖细胞（CPC）来保护心脏免受腰心梗死后梗死（ML）重塑和心力衰竭（HF）的使用。总体目标是阐明调节CPC特性的分子机制，并评估增强CPC功能的治疗效用以优化心脏修复。四个密切相互关联和相互依存的项目将解决该主题的不同方面。项目1（Belli）将阐明CO和NO在调节CPC功能和治疗功效中的作用。中心假设是这些气体是CPC能力的KEV决定因素，并且增加其水平将显着增强CPC介导的心脏修复。项目2（Prabhu）将阐明TNF对CPC能力和修复能力的有害影响。该项目将检验以下假设：通过TNFR1，TNFR2和NF-KB通过差异TNF信号传导在确定肾上腺素能力与心肌生成的命运方面起着关键作用，因此，ML后CPC的恢复能力。项目3（琼斯）将研究蛋白质0-Glcnacylation在调节CPC的基本特性中的作用，并将检验以下假设：0-GLCNAC警报信号在调节CPC增殖，生存，差异，差异和旁核功能中起着至关重要的作用。项目4（Bhatnagar）将决定糖尿病如何影响CPC介导的心肌修复以及如何针对糖尿病心脏进行优化CPC治疗。中心假设是糖尿病通过诱导胰岛素抵抗来破坏CPC的能力。因此，所有四个项目都集中在CPC上。这些项目将得到四个核心的支持，这些核心将提供小鼠手术，细胞移植，CPC培养和表型，病理，流式细胞仪和细胞分选方面的专业知识。这个备受重心的PPG将由多年来有效合作的调查人员领导。他们悠久的合作历史导致了非常适合PPG的密切集成的项目。这些将是最早研究CO和NO，TNF，0-Glcnacylation和2型糖尿病对CPC功能的作用的研究：因此，结果将是全新的，并将促进我们对CPC生物学的理解。此外，这些研究可能为HF患者的CPC治疗的新翻译研究奠定了基础。由于我们已经在HF患者中启动了未修饰的CPC的第一个人类临床试验，因此我们可以迅速将此计划得出的任何见解迅速转化为新的临床研究。