Molecular Regulation of Mammalian Erythro-Megakaryocytic Development

红系(E；红细胞)和巨核细胞(M；血小板前体)谱系是必不可少的 对脊椎动物的健康和生存至关重要，因为它们执行关键功能，如氧气输送 和伤口愈合。因此，他们的发育或功能程序中相对较小的异常会导致危及生命的疾病。这些倾向是不可避免的从 这些细胞的高周转率使它们极易发生故障和 由于增殖和分化之间的不平衡而产生的恶性肿瘤。这些不平衡 反过来又是由于这些过程的各种分子调节器的功能失调所证明的 来自人类患者和动物模型的越来越多的数据。转录本 抑制子Gfi1/1b(生长因子独立性1/1b)及其辅因子LSD1(赖氨酸特异性 去甲基酶和Rcor(REST辅抑制子)蛋白在过去几年中已经出现 作为造血的关键调节因子。然而，他们的职能的真正规模，以及 他们的行动在机电发展中的机械性后果只是名义上的文件。 因此，本建议侧重于阐明这些转录因子的集体功能。 和染色质调节因子及其主要基因/染色质靶标，在协调个体发育过程中 E-M细胞从祖细胞(MEP)规范到分化和分化为 专门的效应细胞。除了对这些紧急事件进行全面概述之外 分子程序和网络的正常发展，这些见解也应该提供一种 合理处理误诊所致造血功能障碍的科学依据 这些主分子的活动。

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.