Transcriptional Regulatory Networks Active in Terminal Erythroid Differentiation

转录调控网络在终末红细胞分化中活跃

• 批准号: 7653613
• 负责人: Shilpa Manohar Hattangadi
• 金额: $ 13.39万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-07-01 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7653613
• 关键词: 1-Phosphatidylinositol 3-Kinase; Anemia; Apoptotic; Binding; Bioinformatics; Biology; Bone Marrow Transplantation; Cells; Childhood; Collaborations; Complementary DNA; Computational algorithm; Consensus Sequence; Coupled; Cytokine Receptors; Dana-Farber Cancer Institute; Data; Data Analyses; Development; Disease; Ensure; Environment; Equipment; Erythrocytes; Erythroid; Erythropoiesis; Erythropoietin; Fanconi' s Anemia; Fetal Liver; Friends; GATA1 gene; Gene Expression; Generic Drugs; Genes; Genome; Goals; Hematologist; Hematology; Institutes; Instruction; Laboratories; Location; Mentorship; Messenger RNA; Methods; Microarray Analysis; Mind; Mitogen-Activated Protein Kinases; Modeling; Modern Medicine; Molecular Profiling; Mus; Pathway interactions; Patients; Phenotype; Phosphotransferases; Population; Process; Property; Proteins; Proto-Oncogene Proteins c-akt; Recording of previous events; Recruitment Activity; Regulation; Research; Research Personnel; Research Project Grants; Research Technics; Resources; Reverse Transcriptase Polymerase Chain Reaction; STAT protein; Science; Signal Pathway; Signal Transduction Pathway; Site; Staging; Testing; Time; Tissues; Training; Transcriptional Regulation; activating transcription factor; base; career; cell type; chromatin immunoprecipitation; cytokine; erythroid differentiation; genetic regulatory protein; human GATA1 protein; in vivo; innovation; insight; interest; leukemia; mRNA Expression; novel; patient population; progenitor; programs; promoter; protein complex; receptor; response; transcription factor

DESCRIPTION (provided by applicant): As a pediatric hematologist, I feel a great need to understand the mechanisms behind the dysregulation of differentiation and proliferation that occur in certain acquired and congenital aplastic anemias and leukemias found in my patient population. The most that modern medicine can often offer these patients is bone marrow transplant. I pursue a career in basic laboratory science in hematology with this quandary in mind, and thus aim to understand the regulation of erythropoiesis. I envision this current research project as intensive training in the biology, research techniques, and information manipulation that are required of an independent investigator in this field, while at the same time, uncovering possible novel genes or new insight into the process of differentiation itself. The research environment, outstanding mentorship, and resources in the form of collaborators, equipment, classes, and colleagues at the Dana Farber Cancer Institute and the Whitehead Institute will uniquely assist me in achieving my career goals. Erythropoietin (Epo) and its cognate receptor, EpoR, ensure the survival of early erythroid precursors in part through induction of the anti-apoptotic protein bcl-xL by the Signal transducer and activator of transcription 5 (Stat5). Epo binding to EpoR results in activation of several signal transduction pathways including the Phosphatidylinositol 3 kinase (Pi3K)/AKT kinase, ras/Mitogen-Activated Protein Kinase (MAPK), and Stat5 pathways, which also initiate the erythroid-specific expression and cellular programs that establish the erythroid phenotype. However, these pathways are not unique to the erythroid lineage: Stat5 activation occurs downstream of numerous cytokine receptors in diverse tissues, regulating vastly different tissue phenotypes. Presumably, these generic, cytokine-induced transcription factors require interaction with pre-existing tissue-specific factors in order to exert their function. Erythroid-important regulatory proteins, GATA1 and FOG (friend of GATA1), are also known to be essential for normal erythropoiesis. In order to elucidate how cytokine-activated and tissue-specific regulatory proteins can collectively initiate the unique expression programs of a tissue, I intend to determine the direct targets of Stat5, GATA1, and FOG in distinct stages of differentiation using chromatin immunoprecipitation and promoter microarrays. I plan to use innovative bioinformatics strategies as well as expression profiling to validate my location data and establish an outline for the transcriptional regulation of erythropoiesis. How genes instruct proteins in different cell types to become unique tissues is probably the basis for how this instruction can go awry in diseases like anemias and leukemias. I plan to understand this program in the biology of red blood cell development, in hopes of discovering new treatments for these disorders.

描述（由申请人提供）： 作为一名儿科血液学家，我觉得非常需要了解在我的患者群体中发现的某些获得性和先天性再生障碍性贫血和白血病中发生的分化和增殖失调背后的机制。现代医学通常能为这些患者提供的最多是骨髓移植。带着这种困惑，我从事血液学基础实验室科学的研究，从而旨在了解红细胞生成的调节。我设想这个目前的研究项目是在生物学，研究技术和信息处理方面的强化培训，这是该领域独立研究者所需的，同时，发现可能的新基因或对分化过程本身的新见解。达纳法伯癌症研究所和怀特黑德研究所的研究环境、出色的导师以及合作者、设备、课程和同事等形式的资源将独特地帮助我实现我的职业目标。 促红细胞生成素（Epo）及其同源受体EpoR部分通过信号转导和转录激活因子5（Stat 5）诱导抗凋亡蛋白bcl-xL来确保早期红细胞前体的存活。Epo与EpoR的结合导致几种信号转导途径的激活，包括磷脂酰肌醇3激酶（Pi 3 K）/AKT激酶、ras/促分裂原活化蛋白激酶（MAPK）和Stat 5途径，其还启动红细胞特异性表达和建立红细胞表型的细胞程序。然而，这些途径并不是红细胞谱系所独有的：Stat 5激活发生在不同组织中的许多细胞因子受体的下游，调节截然不同的组织表型。据推测，这些通用的，精氨酸诱导的转录因子需要与预先存在的组织特异性因子的相互作用，以发挥其功能。红系重要的调节蛋白GATA 1和FOG（GATA 1的朋友）也是正常红细胞生成所必需的。为了阐明精氨酸激活和组织特异性调节蛋白如何共同启动组织的独特表达程序，我打算使用染色质免疫沉淀和启动子微阵列来确定Stat 5，GATA 1和FOG在不同分化阶段的直接靶点。我计划使用创新的生物信息学策略以及表达谱来验证我的位置数据，并建立一个大纲的转录调控红细胞生成。 基因是如何指导不同细胞类型中的蛋白质成为独特的组织的，这可能是这种指导在贫血和白血病等疾病中出错的基础。我计划在红细胞发育的生物学中了解这个项目，希望能发现治疗这些疾病的新方法。