GENETIC & MOLECULAR CONTROL OF E3 UBIQUITIN LIGASES IN STEM DIFFERENTIATION

基因

• 批准号: 8360045
• 负责人: Chozha Vendan Rathinam
• 金额: $ 1.26万
• 依托单位: ROGER WILLIAMS HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-05-01 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8360045
• 关键词: A Mouse; Acute Myelocytic Leukemia; Defect; Development; Dominant-Negative Mutation; Funding; Grant; Hematopoietic; Immunology; Molecular Genetics; Mus; Mutation; Myelogenous; Myeloid Leukemia; National Center for Research Resources; Nature; Neoplasms; PI3K/AKT; Patients; Principal Investigator; Proteins; Proto-Oncogene Protein c-kit; Publishing; Research; Research Infrastructure; Resources; Ring Finger Domain; Signal Transduction Pathway; Source; Stem cells; Therapeutic; United States National Institutes of Health; Work; Wound Healing; base; cost; innovation; mutant; novel; novel strategies; stem; stem cell differentiation; ubiquitin-protein ligase

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. This project is centered on the genetic and molecular control of E3 ubiquitin ligases in stem cell differentiation and neoplasia. The underlying hypothesis, based on the project leader's work recently published in PNAS (2010) and about to be published in Nature Immunology, provides an innovative approach to stem cell differentiation. The hypothesis states that the presence of c-Cbl ring finger mutant protein in HSCs results in altered signal transduction pathways and thereby causes transformation of normal HSCs into leukemic stem cells. In order to prove or disprove this hypothesis, the project leader has developed the following specific aims: 1) Investigate the myeloid differentiation defects in the c-Cbl -/- mice. 2): Identify the hematopoietic compartment that causes AML in c-Cbl A/- mice. 3) Decipher the dominant negative functions of c-Cbl Ring Finger mutant protein in the development of acute myelogenous leukemia (AML). 4) Dissect the requirement of c-Kit/PI3K/AKT/Erk signal transduction pathways in the development of myeloid leukemia in Cbl A/- mice. Overall, this work promises to provide novel ways to understand stem cell differentiation and may also provide directions for therapeutics that may aid the treatment of patients with c-Cbl mutations.

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 而子项目的主要调查员可能是由其他来源提供的， 包括其它NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 该项目的核心是E3泛素连接酶在干细胞分化和肿瘤形成中的遗传和分子控制。基于该项目领导人最近发表在PNAS（2010）上的工作，并即将发表在Nature Immunology上的基本假设，为干细胞分化提供了一种创新方法。该假说指出，c-Cbl环指突变蛋白在HSC中的存在导致改变的信号转导途径，从而导致正常HSC转化为白血病干细胞。为了证明或反驳这一假设，项目负责人制定了以下具体目标： 1)研究c-Cbl -/-小鼠中的髓样分化缺陷。 2）：鉴定在c-Cbl A/-小鼠中引起AML的造血区室。 3)解读c-Cbl环指突变蛋白在急性髓细胞白血病（AML）发生中的显性负性功能。 4)分析c-Kit/PI 3 K/AKT/Erk信号转导通路在Cbl A/-小鼠髓系白血病发生中的需要。 总的来说，这项工作有望提供新的方法来了解干细胞分化，也可能为治疗c-Cbl突变患者提供指导。