Imaging of the Myocardial Microenvironment to Facilitate Stem Cell Engraftment

心肌微环境成像促进干细胞植入

• 批准号: 8319932
• 负责人: Maria Roselle Abraham
• 金额: $ 2.35万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-01-15 至 2014-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8319932
• 关键词: Area; Biology; Bone Marrow Cell Transplantation; Bone Marrow Stem Cell; Cardiac; Cell Adhesion Molecules; Cell Survival; Cell Therapy; Cell Transplantation; Cell Transplants; Cells; Clinical; Clinical Management; Clinical Trials; Decision Making; Disease; Echocardiography; Engraftment; Environment; Future; Goals; Heart Diseases; Histologic; Image; Imaging Techniques; Individual; Integrins; Investigation; Left; Mesenchymal Stem Cells; Metabolism; Modeling; Molecular Target; Myocardial; Myocardial Infarction; Myocardium; Natural regeneration; Nuclear; Patient Selection; Perfusion; Play; Protocols documentation; Rattus; Residual state; Role; Signaling Molecule; Stem cells; Testing; Therapeutic; Time; Tissues; Transplantation; Treatment Efficacy; Up-Regulation; Wit; Work; base; cell type; design; functional improvement; functional outcomes; improved; injured; innovation; insight; molecular imaging; novel strategies; public health relevance; regenerative; repaired; stem cell therapy; success; therapy outcome

DESCRIPTION (provided by applicant): Project Summary Cell therapy is promising for repair of damaged myocardium. But moderate and variable functional benefits in clinical trials emphasize the need for a better understanding of therapeutic mechanisms and for specific imaging techniques which provide insights beyond cardiac function. Frequently, only a small fraction of transplanted cells engrafts in injured myocardium, limiting therapeutic efficacy and providing a potential explanation for the variability of functional benefits. The myocardial microenvironment is considered to be a critical contributor to successful cell engraftment and constitutes a suitable target for molecular imaging. In this proposal, we aim at developing strategies to facilitate successful stem cell engraftment. Our central hypothesis is that molecular-targeted nuclear imaging prior to cell delivery can characterize an optimal biologic environment which is supportive of cell engraftment after delivery, and thus predictive of successful myocardial regeneration. This hypothesis will be tested in 3 specific aims. Quantitative nuclear imaging techniques will be employed to characterize both, myocardial environment, as well as stem cell engraftment in a rat model of myocardial infarction. Therapy outcome will be defined by serial echocardiography and histologic workup. Aim 1 will define the role of tissue perfusion, metabolism and viability in the target area of stem cell delivery, for successful engraftment of cardiac-derived stem cells, an innovative cell type with documented regenerative potential. Aim 2 will investigate the role of expression of the adhesion molecule 1v23 integrin in the target area, as determined by molecular imaging, for successful cardiac stem cell engraftment. In aim 3, cardiac stem cells as a newer cell type will then be compared with the longer established mesenchymal stem cells under conditions of optimal imaging-defined microenvironmental conditions. These studies will provide unique new insights into the contribution of the biologic environment to the success of stem cell based myocardial regeneration. More importantly, they will also provide imaging techniques which may assist in therapeutic decision making by guiding the timing and regional targeting of cell delivery. The ultimate goal of the project is to optimize cell therapeutic benefit based on imaging of individual disease biology. PUBLIC HEALTH RELEVANCE: Project Narrative / Relevance Cardiac stem cell therapy is considered to be a very promising approach for repair of damaged myocardium, but the benefit in clinical trials is currently still variable. In this proposal, molecular imaging techniques are introduced which aim at improving cell therapy by providing information about myocardial microenvironmental conditions which are most suitable for stem cell engraftment. Such biologic imaging strategies have the potential to guide individual therapeutic decisions, and are thus highly relevant to optimize the benefit of stem cell therapy in the clinical management of heart disease.

描述（由申请人提供）： 项目摘要细胞疗法有望修复受损的心肌。但是，在临床试验中，中等和可变的功能益处强调需要更好地了解治疗机制以及对超出心脏功能的见解的特定成像技术。通常，只有一小部分移植细胞植入受伤的心肌中，限制了治疗功效，并为功能益处的变异性提供了潜在的解释。心肌微环境被认为是成功细胞植入的关键因素，并且构成了分子成像的合适靶标。 在此提案中，我们旨在制定策略以促进成功的干细胞植入。我们的中心假设是，细胞递送之前的分子靶向核成像可以表征最佳的生物学环境，该环境支持分娩后细胞植入，因此可以预测成功的心肌再生。该假设将以3个特定目的进行检验。将采用定量核成像技术来表征心肌环境以及大鼠心肌梗塞模型中的干细胞植入。治疗结果将由串行超声心动图和组织学检查定义。 AIM 1将定义组织灌注，代谢和生存能力在干细胞递送目标区域中的作用，以成功地植入心脏衍生的干细胞，这是一种创新的细胞类型。 AIM 2将研究通过分子成像确定的粘附分子1V23整合素在目标区域中的表达作用，以成功地进行心脏干细胞的植入。在AIM 3中，在最佳成像定义的微环境条件下，将将心脏干细胞作为较新的细胞类型与更长的间充质干细胞进行比较。 这些研究将为生物学环境对基于干细胞的心肌再生的成功的贡献提供独特的新见解。更重要的是，它们还将提供成像技术，可以通过指导细胞输送的时间和区域靶向来帮助治疗决策。该项目的最终目标是基于单个疾病生物学的成像来优化细胞治疗益处。 公共卫生相关性： 项目叙事 /相关性心脏干细胞疗法被认为是修复受损心肌的一种非常有前途的方法，但是临床试验中的好处目前仍然可变。在此提案中，引入了分子成像技术，旨在通过提供最适合干细胞植入的心肌微环境条件的信息来改善细胞疗法。这种生物成像策略有可能指导个体的治疗决策，因此与优化干细胞疗法在心脏病临床管理中的好处相关。