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.

该副本是利用资源的众多研究子项目之一 由NIH/NCRR资助的中心赠款提供。对该子弹的主要支持 而且，副投影的主要研究员可能是其他来源提供的 包括其他NIH来源。 列出的总费用可能 代表subproject使用的中心基础架构的估计量， NCRR赠款不直接向子弹或副本人员提供的直接资金。 该项目集中在干细胞分化和肿瘤中E3泛素连接酶的遗传和分子控制上。基于基于项目负责人最近在PNAS（2010）发表并将在自然免疫学上发表的基础假设提供了一种创新的干细胞分化方法。该假设指出，HSC中C-CBL环手指突变蛋白的存在导致信号转导途径改变，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，该项目负责人开发了以下具体目标： 1）研究C-CBL - / - 小鼠中的髓样分化缺陷。 2）：确定在C-CBL A/ - 小鼠中引起AML的造血室。 3）破译C-CBL环手指突变蛋白在急性髓性白血病（AML）发展中的主要负功能。 4）在CBL A/ - 小鼠中髓样白血病的发展中剖析C-KIT/PI3K/AKT/ERK信号转导途径的需求。 总体而言，这项工作有望提供理解干细胞分化的新方法，并且还可能提供有关治疗C-CBL突变患者的治疗方法的方向。