Epigenetic Regulation of Hematopoietic Stem Cell Specification

造血干细胞规格的表观遗传调控

• 批准号: 8000698
• 负责人: Katie L Kathrein
• 金额: $ 5.05万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-12-01 至 2011-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8000698
• 关键词: Biological Models; Cancerous; Cell physiology; Cells; Characteristics; Chromatin; Chromatin Remodeling Factor; Code; Diagnosis; Disease; Epigenetic Process; Family; Gene Expression; Genetic Screening; Hematopoiesis; Hematopoietic; Hematopoietic stem cells; Knowledge; Lesion; Maintenance; Mutation; Normal Cell; Pathway interactions; Patients; Phenotype; Polycomb; Regulation; Role; Stem Cell Development; Stem cells; Therapeutic; Work; Zebrafish; base; cancer cell; chromatin remodeling; leukemia; notch protein; novel; outcome forecast; positional cloning; public health relevance; self-renewal; stem cell fate specification

DESCRIPTION (provided by applicant): Epigenetic Regulation of Hematopoietic Stem Cell Specification SUMMARY Leukemia is a multifaceted disease of disrupted cell function, aberrant gene expression and sustained survival. Some characteristics of leukemia cells are reminiscent of stem cell functions, such as the ability for self-renewal. How cancer cells obtain or re-acquire these characteristics remains unknown, though a role for chromatin remodeling is suggested by the presence of chromatin remodeling factors in translocation products. Similarly, much remains unknown regarding chromatin remodeling in hematopoietic stem cell (HSC) development. Here, we propose to uncover chromatin remodeling factors that regulate HSC specification using zebrafish as a model system. To this end, we will elucidate the role of the Polycomb family of chromatin remodelers in hematopoiesis and establish a hierarchy for Polycomb activity in relation to the Wnt and Notch pathways, both essential in hematopoietic specification and maintenance. We will also conduct a reverse genetic screen using a morpholino-based gene expression knockdown approach to reveal factors necessary for the establishment of HSCs and the HSC epigenetic code. As many of the pathways and regulators associated with leukemia also control hematopoiesis, defining the basic mechanisms of HSC specification and maintenance will illuminate critical factors in normal cell function that cancerous lesions exploit and thus be targeted in therapeutic approaches. PUBLIC HEALTH RELEVANCE: The studies outlined in this proposal will identify factors that alter hematopoietic stem cell development and, when misregulated, may contribute to a leukemic phenotype. Our work aims to identify novel leukemic markers and more accurately determine a diagnosis and prognosis for leukemia patients. Furthermore, knowledge of specific genetic defects may help in selecting a particular course of treatment and may be useful in developing new therapies.

描述（由申请人提供）：造血干细胞规范的表观遗传调节摘要白血病是一种多方面的细胞功能，异常基因表达和持续生存的疾病。白血病细胞的某些特征让人联想到干细胞功能，例如自我更新的能力。癌细胞如何获得或重新获得这些特征仍然未知，尽管染色质重塑的作用是由易位产物中染色质重塑因子的存在提出的。同样，关于造血干细胞（HSC）发育中的染色质重塑，尚不清楚。在这里，我们建议发现使用斑马鱼作为模型系统调节HSC规范的染色质重塑因子。为此，我们将阐明染色质重塑剂在造血中的角色家族的作用，并建立与Wnt和Notch途径相关的多孔活性的层次结构，这在造血规范和维持中都是必不可少的。我们还将使用基于形态的基因表达敲低方法进行反向遗传筛选，以揭示建立HSC和HSC表观遗传密码所必需的因素。由于与白血病相关的许多途径和调节剂也控制造血，定义HSC规范和维持的基本机制将阐明正常细胞功能的关键因素，即癌变病变利用并因此在治疗方法中靶向。 公共卫生相关性：该提案中概述的研究将确定会改变造血干细胞发育的因素，并在误导后可能有助于白血病表型。我们的工作旨在确定新型的白血病标记，并更准确地确定白血病患者的诊断和预后。此外，对特定遗传缺陷的了解可能有助于选择特定的治疗方法，并且可能有助于开发新疗法。