Cell proliferation in hematopoiesis

描述（由申请方提供）：控制细胞增殖是开发的中心主题。在器官形成过程中，细胞分裂的次数是如何受到限制的还不清楚，但已知控制增殖的机制在人类和果蝇中是保守的。而果蝇淋巴腺和血细胞的形成和成熟所必需的大多数基因在人类中是保守的。Toll-NF：B、JAK/STAT、Notch和Ras/Raf等途径调节脊椎动物的造血和果蝇的淋巴腺发育。 我们发现的一个基因控制着细胞分裂的次数。其蛋白质（Zfrp 8）与人类蛋白质（PDCD 2）相似度>50%。果蝇zfrp 8/PDCD 2突变体最明显的表型是造血器官淋巴腺的大量过度生长，伴随着幼虫发育的延迟。我们发现zfrp 8通过控制细胞增殖而不是凋亡来调节淋巴腺生长。我们的研究结果表明，zfrp 8调节果蝇中的Stat水平。zfrp 8的缺失导致与JAK/STAT途径中的功能获得性突变相似的表型。 PDCD 2似乎参与人类造血，并以两种主要形式存在于人类组织中。在骨髓中，我们检测到一种更大形式的蛋白质，这种蛋白质富含含有干细胞的部分。这种蛋白质的一种较小的形式存在于白色血细胞中，其量几乎检测不到。在白血病患者的骨髓和血液中，存在高水平的较小形式的PDCD 2。 我们计划确定zfrp 8在果蝇正常淋巴腺和血细胞发育中的作用，以及在其他组织的生长中的作用，并确定其分子功能。使用各种方法，我们将寻找与zfrp 8功能的其他基因。此外，我们将定义脊椎动物中PDCD 2的基因产物，并将使用血液干细胞和组织培养细胞的体外细胞分化来研究它们在人类造血中的细胞增殖中的功能。 公共卫生相关性：在我们的模型中，果蝇的血细胞发育与人类相似，人类和果蝇中与血液发育有关的许多基因也与血癌有关。 我们已经发现了一个新的基因，zfrp 8，如果缺失，会导致果蝇的血细胞大量过度增殖。在人类中，相同的基因被称为PDCD 2。至少有两种形式的PDCD 2蛋白存在于人类中。在骨髓中有一个较大的形式，而在白色血细胞中我们几乎无法检测到较小的形式。我们建议对PDCD 2/Zfrp 8如何调节果蝇的血细胞形成进行深入研究，并将我们的研究结果作为指导，以研究这一关键基因在人类血液形成中的作用。

DESCRIPTION (provided by applicant): Control of cell proliferation is a central theme in development. How the number of divisions a cell undergoes during organ formation is limited is not well understood, but it is known that the mechanisms controlling proliferation are conserved in humans and Drosophila. And most genes essential for the formation and maturation of the Drosophila lymph gland and hemocytes are conserved in humans. Pathways such as Toll-NF:B, JAK/STAT, Notch, and Ras/Raf regulate hematopoiesis in vertebrates and lymph gland development in flies. A gene we have identified controls the number of divisions a cell undergoes. Its protein (Zfrp8) is >50% similar to the human protein (PDCD2). The most obvious phenotype of fly zfrp8/PDCD2 mutants is a massive overgrowth of the hematopoietic organ, the lymph gland, accompanied by a delay in larval development. We have found that zfrp8 regulates lymph gland growth by controlling cell proliferation and not apoptosis. Our results suggest that zfrp8 regulates Stat levels in Drosophila. Loss of zfrp8 results in a similar phenotype to gain-of-function mutations in the JAK/STAT pathway. PDCD2 appears to be involved in human hematopoiesis and is present in human tissues in two major forms. In bone marrow we detect a larger form of the protein that is enriched in a fraction containing stem cells. A smaller form of the protein is present in barely detectable amounts in white blood cells. In both the bone marrow and blood of leukemia patients, high levels of the smaller form of PDCD2 are present. We plan to define the role of zfrp8 in Drosophila in normal lymph gland and hemocyte development, and in growth of other tissues and to identify its molecular function. Using a variety of approaches we will search for additional genes functioning with zfrp8. Further, we will define the gene products of PDCD2 in vertebrates, and will investigate their function in cell proliferation in human hematopoiesis using in vitro cell differentiation of blood stem cells and tissue culture cells. PUBLIC HEALTH RELEVANCE: Blood cell development in our model, the fruit fly, is similar in humans, and many of the genes in both humans and fruit flies having to do with blood development are also involved in blood cancers. We have identified a new gene, zfrp8 that if absent, results in flies that show an enormous over-proliferation of blood cells. In humans the same gene is called PDCD2. At least two forms of the PDCD2 protein are present in humans. In bone marrow there is a larger form and in white blood cells we can barely detect a smaller form. We propose a thorough study of how PDCD2/Zfrp8 regulates blood cell formation in flies and to use our findings as a guide to investigate the role of this crucial gene in human blood formation.