Protection of Ischemic Myocardium

缺乏对干细胞基本机制的了解限制了目前的治疗方法。在这一更新应用中，我们将重点介绍使用c-kit*心脏祖细胞(CPC)来保护心脏免受心肌梗死(ML)后重构和心力衰竭(HF)的影响。总的目标是阐明调控CPC特性的分子机制，并评估增强CPC功能以优化心脏修复的治疗作用。四个密切相关和相互依存的项目将涉及这一主题的不同方面。项目1(Belli)将阐明CO和NO在调节CPC功能和治疗效果中的作用。中心假设是这些气体是CPC活性的Kev决定因素，增加它们的水平将极大地增强CPC介导的心脏修复。项目2(普拉布)将阐明肿瘤坏死因子对CPC能力和修复能力的有害影响。本项目将检验一种假说，即通过TNFR1、TNFR2和核因子-kB的不同的肿瘤坏死因子信号在决定肾上腺素能和心肌源性的命运，从而决定心肌梗死后的CPC的修复能力方面起着关键作用。项目3(Jones)将研究蛋白质0-GlcN酰化在调节CPC基本性质中的作用，并将检验0-GlcNAc报警信号在调节CPC的增殖、存活、分化和旁分泌功能中发挥关键作用的假设。项目4(Bhatnagar)将确定糖尿病如何影响CPC介导的心肌修复，以及CPC疗法如何优化糖尿病心脏。中心假说是，糖尿病通过诱导胰岛素抵抗来破坏CPC的能力。因此，所有四个项目都将重点放在初级产品上。这些项目将得到四个核心的支持，这四个核心将提供小鼠手术、细胞移植、CPC培养和表型、病理学、流式细胞仪和细胞分类方面的专业知识。这个高度关注的PPG将由多年来卓有成效地合作的调查人员领导。他们长期合作的历史导致了紧密结合的项目，这些项目非常适合PPG。这将是第一次研究CO和NO、肿瘤坏死因子、0-GlcN酰化和2型糖尿病对CPC功能的作用：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，这些研究可能为新的心衰患者CPC疗法的翻译研究奠定基础。由于我们已经在心力衰竭患者中启动了第一个未经修改的CPC的人体临床试验，我们处于有利地位，可以迅速将来自该计划的任何见解转化为新的临床研究。

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.