Aging Effects on Cellular Therapy for Heart Failure

衰老对心力衰竭细胞疗法的影响

• 批准号: 7633192
• 负责人: MOHAMED A GABALLA
• 金额: $ 34.76万
• 依托单位: BANNER SUN HEALTH RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-01-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7633192
• 关键词: 3-Dimensional; Adhesions; Age; Aging; Angiogenic Factor; Animal Model; Blood Vessels; Blood flow; Bone Marrow; CXCR4 gene; Cardiac; Cardiovascular Diseases; Cell Therapy; Cell Transplantation; Cell physiology; Cells; Clinical; Clinical Trials; Collagen; Coronary artery; Data; Doctor of Philosophy; Elderly; Extracellular Matrix; Foundations; Growth Factor; Heart; Heart failure; Hypoxia; Impairment; In Vitro; Infarction; Injection of therapeutic agent; Ischemia; Knowledge; Lead; Literature; Measures; Mediating; Methods; Microarray Analysis; Modeling; Myocardial; Myocardial Infarction; Myocardium; Norway; Perfusion; Play; Population; Predisposition; Process; Rattus; Recovery; Reporting; Research; Research Personnel; Role; Route; Severities; Stem cells; Techniques; Testing; Therapeutic; Tissues; Transplantation; Vascular remodeling; Vascularization; Work; age effect; age related; aged; angiogenesis; base; cytokine; density; depressed; design; experience; improved; in vivo; injured; intravenous injection; laser capture microdissection; neovascularization; overexpression; programs; scaffold; stem; therapeutic angiogenesis; vasculogenesis

DESCRIPTION (provided by applicant): The long term objective of this project is to design a strategy(s) to improve cardiac function in the aged population after myocardial infarction (Ml). The impaired angiogenic capability of the aged heart after Ml may be due to diminished angiogenesis (sprouting of preexisting vessels) and/or vasculogenesis (incorporation of progenitor cells in the newly formed vessels). In contrast to the known impaired angiogenesis, vasculogenesis which is mediated by circulating and/or resident tissue EPCs, is less characterized in the aged heart after Ml. Therefore, determining the role of EPCs in ischemia-induced neovascularization is the main focus of this application. This will provide the foundation to develop an EPC-based strategy to improve cardiac function after Ml in the aged. These EPCs may deliver the needed cytokines for vascularization. Three routes of cell delivery are utilized, intravenous injection, direct injection into the infarct, and delivery using a 3-D collagen scaffold grafted onto the myocardium after Ml. The scaffold approach serves as a model to study cardiac angiogenesis in vivo, and to locally deliver stem cells and/or angiogenic factors to the injured myocardium. Our data, using Brown Norway Fisher 344 cross (BNXF344) rats at different ages (6 weeks, 6 months, and 24 months), indicate that the scaffold initially stabilizes the infarct, promotes angiogenesis, and is replaced by viable tissue. Based on these results, and the current literature, our hypothesis is that cell transplantation of genetically-modified EPCs will enhance ischemia-induced vascularization and will lead to improved cardiac function in the aged after Ml. To test this hypothesis, BNXF344 rat model will be used to determine if the depressed ischemia-induced neovascularization in the aged can be improved using EPC; to elucidate the mechanisms of age-mediated diminished EPCs-contribution to this process; and to determine if overexpression of CXCR4 on EPCs enhances stem cell recruitment to the infarct leading to improve vasculogenesis/cardiac function. Our research will help fill specific gaps in our present knowledge regarding the greater susceptibility to loss of cardiac function after Ml in the elderly and methods to assist recovery. These gaps include: no established treatment exits for the diminished angiogenic capability of the aged heart after Ml; the specific contribution of progenitor cells in this process is unknown; and aging effects on EPCs function are unclear

描述（由申请人提供）：该项目的长期目标是设计一种策略，以改善心肌梗塞（ML）后老年人群的心脏功能。 ML后老年心脏的血管生成能力受损可能是由于血管生成减少（先前存在的血管发芽）和/或血管生成（在新形成的血管中掺入祖细胞）。与已知的受损血管生成相反，通过循环和/或驻留组织EPC介导的血管生成在ML后在老年心脏中的特征较少。因此，确定EPC在缺血引起的新血管形成中的作用是该应用的主要重点。这将为建立基于EPC的策略以改善ML年龄的策略提供基础。这些EPC可能会提供所需的细胞因子来进行血管化。使用了三种细胞输送途径，静脉注射，直接注射到梗塞中，并使用3D胶原蛋白支架接枝到ML后移植到心肌上。脚手架方法是研究体内心脏血管生成的模型，并局部将干细胞和/或血管生成因子向受伤的心肌传递。我们的数据使用北方挪威Fisher 344横章（BNXF344）大鼠在不同年龄（6周，6个月和24个月）的大鼠，表明支架最初稳定梗塞，促进血管生成，并由可行的组织取代。基于这些结果和当前的文献，我们的假设是遗传改性EPC的细胞移植将增强缺血诱导的血管化，并在ML后的老年人中改善心脏功能。为了检验这一假设，将使用BNXF344大鼠模型来确定使用EPC可以改善衰老的缺血诱导的新生血管形成。为了阐明年龄介导的EPC-contribution的机制；并确定CXCR4在EPCS上的过表达是否会增强干细胞募集到梗塞，从而改善血管生成/心脏功能。我们的研究将有助于填补我们目前的知识中的特定空白，即ML在老年人中对心脏功能丧失的敏感性和帮助恢复的方法。这些差距包括：没有确定的治疗方法，即ML后老年心脏的血管生成能力降低；祖细胞在此过程中的特定贡献尚不清楚。对EPC功能的衰老影响尚不清楚