Rebuilding the Failing Heart

重建失败的心

• 批准号: 7918141
• 负责人: Piero Anversa
• 金额: $ 259.14万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-20 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7918141
• 关键词: Animal Model; Biology; Blood Vessels; Blood capillaries; Bone Marrow; Cardiac; Cardiac Myocytes; Categories; Cell Lineage; Cell physiology; Cells; Coronary; Coronary Circulation; Coronary artery; Data; Differentiation and Growth; Endothelial Cells; Heart; Hematopoietic stem cells; Human; Knowledge; Lesion; Molecular; Muscle Cells; Myocardium; Organ; Pathway interactions; Phenotype; Program Research Project Grants; Property; Smooth Muscle Myocytes; Stem cells; Structure; Testing; Therapeutic; capillary; genetic manipulation; muscle form; pre-clinical; primitive cell; reconstitution; regenerative; repaired

DESCRIPTION (provided by applicant): The common theme of this Program Project Grant (PPG) is the acquisition of fundamental knowledge on the growth and differentiation of progenitor cells (PCs). Understanding PC function and the relationship between cardiac PCs and bone marrow progenitor cells (BMPCs) is critical for the implementation of PC categories in the treatment of the chronically decompensated human heart. Theoretically, in a manner comparable to hematopoietic stem cells that repopulate and completely reconstitute the ablated bone marrow, cardiac PCs may be capable of rebuilding the damaged myocardium and converting a severely diseased failing heart into a physiologically functional heart. To accomplish these objectives, we need profound understanding of the biology of resident PCs and we have to determine whether the cardiac PC pool includes distinct classes of primitive cells which have powerful but distinct vasculogenic and myogenic properties. The recognition of a coronary vascular progenitor cell (VPC) that differentiates predominantly into smooth muscle cells and endothelial cells would suggest that the heart has the ability to create the various portions of the coronary circulation, from conductive coronary arteries to capillary structures. Similarly, the characterization of a myocyte progenitor cell (MPC) that acquires prevalently the cardiomyocyte phenotype would suggest that the opportunity exists to restore extensive losses of muscle mass. Various proportions of VPCs and MPCs may be utilized according to the needs of the organ and the uniqueness of the cardiac lesion. By necessity, this information will be obtained initially in small animal models (Project 1), which are particularly suitable for genetic manipulations relevant to the characterization of the effector pathways that regulate the activation and differentiation of PC classes into specific cardiac cell lineages. Concurrently, the presence and therapeutic potential of VPCs and MPCs will be established in large animal models (Projects 2 and 3) to obtain relevant preclinical data. Finally, whether the decompensated human heart possesses functionally competent VPCs and MPCs and whether molecular strategies can be implemented to interfere with the fate of PC categories and enhance their regenerative capacity will be tested (Project 4). Ultimately, the identity of cardiac PC classes and the molecular mechanisms involved in the activation and differentiation of these primitive cells into separate cardiogehic phenotypes will be evaluated to define the efficacy of these cells for the repair of the chronically failing heart.

描述（由申请人提供）： 该项目资助（PPG）的共同主题是获得祖细胞（PC）生长和分化的基础知识。了解PC功能和心脏PC和骨髓祖细胞（BMPC）之间的关系是至关重要的PC类在治疗慢性失代偿的人类心脏的实施。从理论上讲，以一种与造血干细胞再生和完全重建消融骨髓的方式相当的方式，心脏PC可能能够重建受损的心肌，并将严重疾病的衰竭心脏转化为生理功能正常的心脏。为了实现这些目标，我们需要深入了解居民PC的生物学，我们必须确定心脏PC池是否包括不同类别的原始细胞，这些原始细胞具有强大但独特的血管生成和肌生成特性。冠状动脉血管祖细胞（VPC）主要分化为平滑肌细胞和内皮细胞，这表明心脏有能力产生冠状动脉循环的各个部分，从传导冠状动脉到毛细血管结构。类似地，获得预先获得心肌细胞表型的肌细胞祖细胞（MPC）的表征将表明存在恢复肌肉质量的广泛损失的机会。根据器官的需要和心脏病变的独特性，可以使用各种比例的VPC和MPC。根据需要，这些信息最初将在小动物模型中获得（项目1），这些模型特别适合于与调控PC类活化和分化为特定心脏细胞谱系的效应子途径表征相关的遗传操作。同时，将在大型动物模型（项目2和3）中确定VPC和MPC的存在和治疗潜力，以获得相关的临床前数据。最后，失代偿的人类心脏是否具有功能上胜任的VPC和MPC，以及是否可以实施分子策略来干扰PC类别的命运并增强其再生能力，将进行测试（项目4）。最终，将评估心脏PC类的身份和参与这些原始细胞活化和分化为单独的心脏表型的分子机制，以确定这些细胞修复慢性衰竭心脏的功效。