Midwestern Progenitor Cell Consortium

描述（由申请人提供）： 血液和心血管疾病既常见又致命。这些疾病是慢性的、使人衰弱的，需要新的治疗方法。血液和心血管程序具有许多重叠的特征，因为两者都是侧板中胚层衍生物，并且都受到转录因子、信号级联和细胞外线索的高度交叉网络的共同调节。我们机构开展的项目将定义促进干细胞和祖细胞采取造血和心血管细胞命运的网络中的关键调控节点，旨在改善临床选择。我们将破译促进干/祖细胞规范和分化为心脏、血管和造血限制谱系的细胞内、细胞外和旁分泌因子。在这些项目中，我们将利用一系列工具和新兴技术，包括转基因小鼠模型、基因工程胚胎和诱导多能干细胞、克隆心脏祖细胞群、脱细胞心脏和最先进的高分辨率成像/光谱技术，这将促进我们以及威斯康星大学合作者和 NHLBI 祖细胞生物学研究联盟相关人员的研究。该提案的总体目标是机械地破译控制干细胞向心血管和造血谱系的规范和分化的细胞内和细胞外网络。为了实现这一总体目标，我们将开展以下项目： 项目#1：定义 hESC 和 hiPSC 衍生中胚层中造血程序的转录机制。项目#2：定义 mES/EB、hESC、hIPSC 和心脏祖细胞中指定心血管程序的转录和信号网络。项目#3：定义细胞外信号，包括指导心血管分化和功能的细胞基质相互作用。项目#4：确定源自 hESC 和 hiPSC 的用于心肌再生的最佳细胞群。这些合作研究的结果将作为血液疾病和心血管疾病的新兴疗法的平台。

DESCRIPTION (provided by applicant): Blood and cardiovascular diseases are both common and deadly. These diseases are chronic, debilitating and they warrant novel therapies. The blood and cardiovascular programs have a number of overlapping features as both are lateral plate mesodermal derivatives and both are coregulated by highly intersecting networks of transcription factors, signaling cascades and extracellular cues. The projects undertaken at our institution will define the key regulatory nodes in the networks that promote stem cells and progenitor cells to adopt a hematopoietic and cardiovascular cell fate - with an aim toward improving clinical options. We will decipher the intracellular, extracellular and paracrine factors that promote stem/progenitor cell specification and differentiation to cardiac, vascular and hematopoietic restricted lineages. In these projects, we will utilize an array of tools and emerging technologies including transgenic mouse models, genetically engineered embryonic and induced pluripotent stem cells, clonal cardiac progenitor cell populations, the decellularized heart, and state-of-the-art high resolution imaging/spectroscopy technologies, which will facilitate our studies and those of our collaborators at the University of Wisconsin and those associated with the NHLBI Progenitor Cell Biology Research Consortium. The overall goal of this proposal is to mechanistically decipher the intracellular and extracellular networks that govern specification and differentiation of stem cells to the cardiovascular and hematopoietic lineages. To address this overall goal, we will pursue the following projects: Project #1: To define the transcriptional mechanisms that specify the hematopoietic program in hESC- and hiPSC-derived mesoderm. Project #2: To define the transcriptional and signaling networks that specify the cardiovascular program In mES/EBs, hESC, hIPSC, and cardiac progenitors. Project #3: To define the extracellular cues including cell matrix interactions that direct cardiovascular differentiation and function. Project #4: To define the optimal cell populations derived from hESCs and hiPSCs for myocardial regeneration. The results of these collaborative studies will serve as a platform for emerging therapies for blood disorders and cardiovascular disease.