Cell proliferation in hematopoiesis

造血过程中的细胞增殖

• 批准号: 8260563
• 负责人: Ruth M STEWARD
• 金额: $ 28.15万
• 依托单位: RUTGERS, THE STATE UNIV OF N.J.
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-07 至 2014-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8260563
• 关键词: Apoptosis; Biochemical Pathway; Biological Metamorphosis; Blood; Blood Cells; Bone Marrow; CD34 gene; Cell Culture Techniques; Cell Differentiation process; Cell Proliferation; Cells; Co-Immunoprecipitations; Cultured Cells; Development; Drosophila genus; Embryo; Embryonic Development; Gene Proteins; Genes; Genetic; Growth; Hematopoiesis; Hematopoietic; Hematopoietic Neoplasms; Hemocytes; Hemolymph; Human; Hyperplasia; In Vitro; Infection; Investigation; Length; Leukocytes; Mammalian Cell; Modeling; Molecular; Mus; Nature; Organ; Organism; Pathway interactions; Patients; Phenotype; Process; Proteins; Ras/Raf; Role; Staging; Stem cells; Study models; System; Tertiary Protein Structure; Tissues; Umbilical Cord Blood; Vertebrates; blood forming organ; cancer cell; fly; gain of function mutation; gene function; gland development; human tissue; knock-down; leukemia; lymph nodes; mutant; notch protein; public health relevance; research study; response; stem cell fate; tissue/cell culture; yeast two hybrid system

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.

描述(申请人提供)：控制细胞增殖是发展中的一个中心主题。细胞在器官形成过程中经历的分裂数量如何有限还不是很清楚，但众所周知，控制增殖的机制在人类和果蝇中是保守的。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都是保守的。Toll-NF：B、JAK/STAT、Notch和Ras/Raf等途径调控脊椎动物的造血和果蝇的淋巴腺发育。我们已经确定的一种基因控制着细胞经历的分裂数量。它的蛋白质(Zfrp8)与人类蛋白质(PDCD2)有50%的相似性。苍蝇zfrp8/PDCD2突变体最明显的表型是造血器官淋巴腺大量过度生长，伴随着幼虫发育的延迟。我们发现，zfrp8通过控制细胞增殖而不是细胞凋亡来调节淋巴腺的生长。我们的结果表明，zfrp8调节果蝇体内的Stat水平。Zfrp8的缺失导致了类似于JAK/STAT通路中功能获得突变的表型。PDCD2似乎参与了人类的造血，并以两种主要形式存在于人体组织中。在骨髓中，我们检测到一种更大形式的蛋白质，这种蛋白质富含在含有干细胞的部分中。一种较小形式的蛋白质存在于白细胞中，几乎检测不到数量。在白血病患者的骨髓和血液中，都存在高水平的较小形式的PDCD2。我们计划确定zfrp8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zfrp8一起起作用的其他基因。进一步，我们将确定脊椎动物中PDCD2的基因产物，并将利用血液干细胞和组织培养细胞的体外分化来研究它们在人类造血细胞增殖中的作用。 公共卫生相关性：我们的模型果蝇的血细胞发育与人类相似，人类和果蝇中许多与血液发育有关的基因也与血癌有关。我们已经确定了一种新的基因zfrp8，如果没有这种基因，会导致果蝇出现血细胞的巨大过度增殖。在人类身上，同样的基因被称为PDCD2。至少有两种形式的PDCD2蛋白存在于人类体内。在骨髓中有较大的形式，而在白细胞中我们几乎检测不到较小的形式。我们建议对PDCD2/Zfrp8如何调节果蝇的血细胞形成进行深入研究，并以我们的发现为指导，研究这一关键基因在人类血液形成中的作用。