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: 8527319
• 负责人: Maria Roselle Abraham
• 金额: $ 2.64万
• 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/8527319
• 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心肌。但临床试验中适度和可变的功能益处强调需要更好地了解治疗机制和特定成像技术，以提供超越心脏功能的见解。通常，只有一小部分移植细胞植入受损的心肌中，限制了治疗效果并为功能益处的可变性提供了潜在的解释。心肌微环境被认为是细胞成功植入的关键因素，并构成分子成像的合适目标。 在本提案中，我们的目标是制定促进干细胞成功植入的策略。我们的中心假设是，细胞递送前的分子靶向核成像可以表征最佳的生物环境，该环境支持递送后的细胞植入，从而预测成功的心肌再生。该假设将在 3 个具体目标中得到检验。定量核成像技术将用于表征心肌梗塞大鼠模型中的心肌环境以及干细胞植入。治疗结果将通过连续超声心动图和组织学检查来确定。 目标 1 将定义组织灌注、代谢和活力在干细胞递送目标区域中的作用，以成功植入心脏来源的干细胞，这是一种具有记录再生潜力的创新细胞类型。目标 2 将研究通过分子成像确定的目标区域中粘附分子 1v23 整合素的表达对于心脏干细胞成功植入的作用。在目标 3 中，心脏干细胞作为一种较新的细胞类型，将在最佳成像定义的微环境条件下与建立时间较长的间充质干细胞进行比较。 这些研究将为生物环境对基于干细胞的心肌再生成功的贡献提供独特的新见解。更重要的是，他们还将提供成像技术，通过指导细胞递送的时间和区域靶向来协助治疗决策。该项目的最终目标是根据个体疾病生物学成像来优化细胞治疗效果。 公共卫生相关性： 项目叙述/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，但目前临床试验中的益处仍然存在差异。在该提案中，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治疗。这种生物成像策略有可能指导个体治疗决策，因此与优化干细胞治疗在心脏病临床管理中的益处高度相关。