Protection of Ischemic Myocardium

缺乏对基本干细胞机制的理解限制了目前的治疗方法。在该更新申请中，我们将集中于使用c-kit* 心脏祖细胞（CPC）来保护心脏免受心肌梗死（MI）后重构和心力衰竭（HF）。总体目标是阐明调节CPC性质的分子机制，并评估增强CPC功能以优化心脏修复的治疗效用。四个密切相关和相互依赖的项目将解决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。核心假设是这些气体是CPC能力的kev决定因素，并且增加它们的水平将显著增强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：经由TNFR 1、TNFR 2和NF-κ B的差异TNF信号传导在确定肾上腺素能与心肌源性命运中起关键作用，并且因此，在MI后CPC的修复能力中起关键作用。项目3（Jones）将研究蛋白质0-GlcNAc化在调节CPC基本特性中的作用，并将检验0-GlcNAc警报信号在调节CPC增殖、存活、分化和旁分泌功能中起关键作用的假设。项目4（Bhatnagar）将确定糖尿病如何影响CPC介导的心肌修复，以及如何优化CPC治疗糖尿病心脏。核心假设是糖尿病通过诱导胰岛素抵抗破坏CPC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培养和表型分析，病理学，流式细胞术和细胞分选方面的专业知识。这个高度集中的PPG将由多年来富有成效地合作的研究人员领导。他们长期的合作历史导致了紧密集成的项目，非常适合PPG。这些将是第一个研究CO和NO，TNF，0-GlcNAc酰化和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CPC治疗HF患者的新的转化研究奠定基础。由于我们已经在HF患者中启动了未经修饰的CPC的首次人体临床试验，因此我们有能力将该计划中的任何见解快速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.