Role of the NO-CO Module in Regulating CPC Function

NO-CO 模块在调节 CPC 功能中的作用

• 批准号: 8688305
• 负责人: Roberto Bolli
• 金额: $ 32.06万
• 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
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8688305
• 关键词: Apoptosis; Apoptotic; Carbon Monoxide; Cardiac; Cell Survival; Cell Therapy; Cell Transplants; Cell physiology; Cells; Cellular biology; Chemotaxis; Clinical Research; Competence; Deet; Dimensions; Effectiveness; Evolution; Functional disorder; Funding; Future; Gene Transfer; Generations; Genetic; Genetic Transcription; Goals; Heart failure; Heme; Human; In Vitro; Instruction; Ischemia; Left Ventricular Remodeling; Length; Measures; Mediating; Mediator of activation protein; Minority; Modeling; Molecular; Mus; Myocardial; Myocardial Infarction; Myocardial Ischemia; Myocardium; Nitric Oxide; Nitric Oxide Donors; Nitric Oxide Synthase; Oxidative Stress; Patients; Phase I Clinical Trials; Proteins; Proto-Oncogene Protein c-kit; Reactive Oxygen Species; Resistance; Role; Stem cells; Structure; Superoxide Dismutase; Telomerase; Testing; Therapeutic; Translations; Transplantation; Up-Regulation; Work; cardiac repair; clinical application; cytokine; extracellular; gain of function; heme oxygenase-1; human NOS2A protein; in vivo; inhibitor/antagonist; loss of function; novel strategies; oxidative damage; phase 1 study; pre-clinical; preconditioning; prevent; programs; senescence; telomere; transcription factor

The discovery of cardiac progenitor cells (CPCs) provides a potential new approach to the treatment of heart failure (HF), The initial results of our first-in-humans clinical study of CPCs in patients with HF (SCIPIO) are encouraging. However, CPC-based therapies are severely limited by the fact that almost all (at least 97%) of the transplanted CPCs die shortly after transplantation. This implies that increasing the survival of transplanted cells by preventing apoptosis will enhance the efficacy of CPC therapy. In the current funding period of this Program Project, we have found that carbon monoxide (CO) and nitric oxide (NO) exert powerful anti-apoptotic actions and form a closely inter-related functional module (CO-NO module), which is regulated by heme oxygenase-1 (HO-1), extracellular superoxide dismutase (ecSOD), and inducible NO synthase (iNOS). We will exploit this discovery to enhance cell-based therapies. The overall goal of Project 1 is to elucidate the role of the CO-NO module in regulating CPC function and to evaluate its therapeutic utility after myocardial infarction (Ml). We propose that augmenting this module will greatly potentiate the effectiveness of transplanted CPCs and dramatically enhance CPC-mediated cardiac repair. This Project represents the natural evolution of our previous work in this Program Project; having discovered that the CO- NO module affors powerful protection against mmyocardial ischemia, we will now build on this work to enhance the reparative ability of CPCs. In Aim 1, we will determine the roles of HO-1 and CO in modulating CPC function. In Aim 2, we will establish the role of ecSOD in regulating CPC function and mediating HO-1- induced protection of CPCs. In Aim 3, we will determine the role of NO in modulating CPC function and the role of HO-1 and ecSOD in mediating the effects of NO on CPCs. Using both gain- and loss-of-function approaches, in all three Aims we will systematically evaluate fundamental parameters of CPC competence in vitro and the ability of CPCs to repair cardiac damage in vivo in a murine model of post-MI LV remodeling and dysfunction. In Aim 4. we will elucidate the molecular mechanisms whereby CO and NO upregulate ecSOD, and NO upregulates HO-1 and ecSOD in CPCs, focusing on the transcription factor Nrf2. These will be the first studies to examine the role of CO and NO, and their supporting proteins HO-1, ecSOD, and INOS, in modulating CPC function. The results will be entirely new and will add a new dimension to our understanding of CPC biology. In addition, these studies will provide proof-of-principle for the therapeutic utility of manipulations that potentiate the CO-NO module in CPCs, which may lay the groundwork for future trials of genetically or pharmacologically enhanced CPCs in patients with HF.

心脏祖细胞（cardiac progenitor cells，CPC）的发现为心力衰竭（heart failure，HF）的治疗提供了一种潜在的新方法。然而，基于CPC的疗法受到几乎所有（至少97%）移植的CPC在移植后不久死亡的事实的严重限制。这意味着通过防止细胞凋亡来增加移植细胞的存活将增强CPC治疗的功效。在本项目资助期间，我们发现一氧化碳（CO）和一氧化氮（NO）具有强大的抗凋亡作用，并形成一个密切相关的功能模块（CO-NO模块），该模块受血红素加氧酶-1（HO-1）、细胞外超氧化物歧化酶（ecSOD）和诱导型NO合酶（iNOS）的调节。我们将利用这一发现来增强基于细胞的疗法。项目1的总体目标是阐明CO-NO模块在调节CPC功能中的作用，并评估其在心肌梗死（MI）后的治疗效用。我们建议，增加这个模块将大大增强移植CPC的有效性，并显着提高CPC介导的心脏修复。本项目代表了我们在本项目中先前工作的自然演变;已经发现CO-NO模块提供对心肌缺血的强大保护，我们现在将在此工作的基础上增强CPC的修复能力。在目的1中，我们将确定HO-1和CO在调节CPC功能中的作用。目的2：探讨ecSOD在CPC功能调节和HO-1介导的CPC保护中的作用。目的3：研究NO对CPC功能的调节作用，以及HO-1和ecSOD在NO对CPC作用中的作用。使用功能获得和功能丧失方法，在所有三个目标中，我们将系统地评估CPC体外能力的基本参数以及CPC在MI后LV重塑和功能障碍的小鼠模型中修复体内心脏损伤的能力。目标4.我们将阐明CPCs中CO和NO上调ecSOD，NO上调HO-1和ecSOD的分子机制，重点是转录因子Nrf 2。这将是第一个研究CO和NO，以及它们的支持蛋白HO-1，ecSOD和INOS在调节CPC功能中的作用。结果将是全新的，并将为我们对CPC生物学的理解增添新的维度。此外，这些研究将为加强CPC中CO-NO模块的操作的治疗效用提供原理证明，这可能为将来在HF患者中进行基因或生物学增强的CPC试验奠定基础。