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，使人虚弱，它们需要新的治疗方法。血液和心血管项目有许多重叠的特征，因为两者都是侧板中胚层衍生物，都受到高度交叉的转录因子、信号级联和细胞外信号网络的共同调节。我们机构开展的项目将定义促进干细胞和祖细胞采用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。我们将破译细胞内、细胞外和旁分泌因子，这些因子促进干细胞/祖细胞的指定和分化为心脏、血管和造血限制的谱系。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、克隆性心脏祖细胞种群、去细胞心脏，以及最先进的高分辨率成像/光谱技术，这将促进我们和我们在威斯康星大学的合作者以及与NHLBI前体细胞生物学研究联盟相关的研究。这项提议的总体目标是从机械上破译细胞内和细胞外网络，这些网络管理干细胞向心血管和造血祖细胞的指定和分化。为了解决这一总体目标，我们将进行以下项目：项目1：定义在hESC和HiPSC来源的中胚层中指定造血计划的转录机制。项目2：定义在MES/EBS、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：确定用于心肌再生的hESCs和hPSCs的最佳细胞群。这些合作研究的结果将成为治疗血液疾病和心血管疾病的新疗法的平台。

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.