Molecular Regulation of Mammalian Erythro-Megakaryocytic Development

红细胞（E;红细胞）和巨核细胞（M;血小板前体）谱系是必需的， 对脊椎动物的健康和生存能力至关重要，因为它们执行氧气输送等关键功能 和伤口愈合。因此，在其发育或功能程序中相对较小的畸变导致危及生命的疾病。这些倾向是一个不可避免的脱落， 这些细胞的高周转率使它们极易发生故障， 由增殖和分化之间的不平衡引起的恶性肿瘤。这些不平衡 反过来是由于这些过程的各种分子调节剂的功能障碍， 越来越多的来自人类患者和动物模型的数据。转录 抑制因子Gfi 1/1b（生长因子非依赖性1/1b）及其辅因子LSD 1（赖氨酸特异性 在过去的几年中，已经出现了脱甲基酶1）和Rcor（REST辅阻遏物）蛋白 作为造血的关键调节器。然而，它们的功能的真正规模， 他们在E-M开发中的行为的机械后果只在名义上被记录下来。 因此，本建议的重点是阐明这些转录的集体功能， 和染色质调节因子及其主要基因/染色质靶点，在协调个体发育中起着重要作用。 E-M细胞从祖细胞（MEP）特化到它们的分化和分化为 专门的效应细胞。除了全面概述这些新兴的 分子程序和网络的正常发展，这些见解也应该提供一个 合理的科学基础，以管理造血功能紊乱造成的错误 这些主要分子的活动。

Erythroid (E; red blood cell) and megakaryocytic (M; platelet precursor) lineages are essential and vital to vertebrate health and viability as they performing crucial functions like oxygen delivery and wound healing. Consequently, relatively minor aberrations in their developmental or functional programs lead to life threatening disorders. These proclivities are an inevitable fall out of the high turnover rate of these cells that makes them acutely susceptible to malfunctions and malignancies arising from imbalances between proliferation and differentiation. These imbalances in turn are due to the dysfunctions of various molecular regulators of these processes as evidenced by a growing body of data from human patients and animal models. The transcriptional repressors Gfi1/1b (growth factor independence 1/1b) and their cofactors LSD1 (lysine specific demethylase1) and Rcor (REST corepressor) proteins have emerged over the past several years as critical regulators of hematopoiesis. Yet the true scale of their functions, and mechanistic ramifications of their actions, in E-M development have only been nominally documented. Therefore, this proposal focuses on elucidating the collective functions of these transcriptional and chromatin regulators and their principal gene/chromatin targets, in orchestrating the ontogeny of E-M cells from progenitor (MEP) specification to their divergence and differentiation into specialized effector cells. In addition to producing a comprehensive overview of these emergent molecular programs and networks in normal development, these insights should also provide a rational scientific basis for managing hematopoietic disorders resulting from the errant activities of these master molecules.