Cardiac progenitor fates and directed reprogramming of non-cardiac cells

心脏祖细胞的命运和非心脏细胞的定向重编程

• 批准号: 7677098
• 负责人: EDWARD E MORRISEY
• 金额: $ 3.94万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-02-01 至 2009-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7677098
• 关键词: Accounting; Adopted; Adult; Area; Biology; Cardiac; Cardiac Myocytes; Cardiovascular system; Cell Differentiation process; Cell Lineage; Cells; Characteristics; Commit; Data; Development; Embryo; Endothelium; Epicardium; Epigenetic Process; Goals; Heart; Knowledge; Maps; Mesoderm Cell; Muscle Cells; Myocardium; Physiology; Population; Regenerative Medicine; Research; Research Personnel; Role; Signal Transduction; Vascular Smooth Muscle; cell type; empowered; in vivo; induced pluripotent stem cell; notch protein; progenitor; prospective; self-renewal; stem cell biology

DESCRIPTION (provided by applicant): This proposal seeks to utilize dramatic new advances in both epigenetic reprogramming and cardiovascular lineage/cell fate determination to inform and empower our ability to harness regenerative medicine for cardiovascular therapies. In recent years, new discoveries have significantly altered our understanding of how the heart forms. It is now clear that several cardiac progenitor populations can be identified that contribute to the adult myocardium, though the precise relationships among these populations and their distinct lineages potential remain poorly defined. The description of induced pluripotential (iPS) cells demands a rethinking of cellular plasticity and suggests the possibility of reprogramming a differentiated cell to adopt the characteristics and potential of a cardiac progenitor and subsequently a functional myocyte (16, 21, 22, 32). However, a major challenge of this research is whether reprogramming of adult cells can be directed in such a way as to dedifferentiate to a committed precardiac progenitor state without reprogramming fully to a pluripotential state. We propose to assemble a team of collaborative investigators with established expertise in cardiac development and physiology, stem cell biology and regenerative medicine to elucidate and define progressive lineage restriction during embryonic cardiac development, including the roles of Wnt and Notch signaling in cardiac progenitor biology, and to define the necessary factors for directed reprogramming of adult cells to the cardiac progenitor state. We will pursue the following aims: Compare and contrast the prospective fates of distinct cardiovascular progenitor populations in vivo to allow for an accurate spatial and temporal accounting of genetically defined populations to generate mature cardiovascular cell types during progressive lineage restriction. Characterize the ability of Wnt and Notch signaling to regulate self-renewal and differentiation in different cardiovascular progenitor subpopulations. Utilizing known information and data gathered from studies in areas 1 and 2, determine the necessary factors for producing induced cardiac progenitor (iCPC) cells and their subsequent differentiation into functional cardiac myocytes.

描述（由申请人提供）：该提案旨在利用表观遗传重编程和心血管谱系/细胞命运确定方面的重大新进展，以告知并增强我们利用再生医学进行心血管治疗的能力。 近年来，新的发现大大改变了我们对心脏如何形成的理解。 现在很清楚的是，可以确定几个心脏祖细胞群体，有助于成人心肌，虽然这些群体之间的精确关系和他们不同的谱系潜力仍然很难定义。 对诱导多能性（iPS）细胞的描述需要重新思考细胞可塑性，并表明重新编程分化细胞以采用心脏祖细胞的特征和潜力并随后成为功能性肌细胞的可能性（16，21，22，32）。 然而，这项研究的一个主要挑战是，成年细胞的重编程是否可以以这样的方式进行，即去分化为定向心前祖细胞状态，而无需完全重编程为多能状态。 我们建议组建一个具有心脏发育和生理学，干细胞生物学和再生医学专业知识的合作研究人员团队，以阐明和定义胚胎心脏发育过程中的渐进性谱系限制，包括Wnt和Notch信号传导在心脏祖细胞生物学中的作用，并确定将成体细胞定向重编程为心脏祖细胞状态的必要因素。 我们将努力实现以下目标： 比较和对比不同的心血管祖细胞群体在体内的预期命运， 允许对基因定义的种群进行准确的空间和时间核算， 成熟的心血管细胞类型进行性谱系限制。 表征Wnt和Notch信号传导调节细胞中自我更新和分化的能力， 不同的心血管祖细胞亚群。 利用从领域1和领域2的研究中收集的已知信息和数据，确定必要的 用于产生诱导的心脏祖细胞（iCPC）和它们随后分化成 功能性心肌细胞