TYORISINE PHOSPHATASE SHP2 IN HEMATOPOIETIC STEM CELL PROPERTY MAINTENANCE

酪氨酸磷酸酶 SHP2 在造血干细胞特性维持中的作用

• 批准号: 8360134
• 负责人: Wentian Yang
• 金额: $ 21.04万
• 依托单位: RHODE ISLAND HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8360134
• 关键词: 1-Phosphatidylinositol 3-Kinase; Accounting; Adolescent; Affect; Alleles; Basic Science; Bone Marrow; Cell Differentiation process; Cell Maintenance; Cell Proliferation; Cells; Clinical Research; Data; Disease; Erythroid; Funding; Goals; Grant; Granulocyte-Macrophage Colony-Stimulating Factor; Growth; Hematopoiesis; Hematopoietic; Hematopoietic stem cells; Human; Knowledge; Macrophage Colony-Stimulating Factor; Maintenance; Marrow; Molecular; Mus; Mutant Strains Mice; Mutation; Myelogenous; Myeloid Cells; Myelopoiesis; National Center for Research Resources; Non-Receptor Type 11 Protein Tyrosine Phosphatase; PTPN11 gene; Play; Principal Investigator; Property; Protein Tyrosine Phosphatase; Regenerative Medicine; Research; Research Infrastructure; Resources; Role; Signal Pathway; Signal Transduction; Source; Src homology 2 domain-containing, transforming protein 1; Staging; System; United States National Institutes of Health; aged; base; cost; granulocyte; insight; macrophage; progenitor; response; self-renewal; stem cell biology

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. The long term goal of this study is to elucidate the function of protein tyrosine phosphatases in normal hematopoiesis and hematopoietic disorders. We will focus on the role of the Src homology 2 (SH2) domain containing protein tyrosine phosphatase Shp2 (PTPN11) based on our recent data collected from hematopoietic cell/stage-specific Shp2 deficient mice. We previously generated a Ptpn11 floxed allele, inducible deletion of Shp2 in hematopoietic cells via "Cre-loxP" system causes marrow aplasia, substantial reduction of hematopoietic stem cells (HSC) and decreased colony formation of myeloid and erythroid lineages. Shp2 mutant mice appear smaller, not healthy and were severely anemic. In contrast, mice lacking Shp2 expression since granulocyte (G)-macrophage (M) progenitor (GMP) stage, appear normal, but developed osteopetreosis as they aged. Marrow cells from these mutant mice show reduction in the number and size of CFU-M and CFU-GM colonies. Bone marrow derived macrophages (BMM) lacking Shp2 expression display retarded growth and defective Ras/Erk activation in response to both macrophage-colony stimulating factor (M-CSF) and granulocyte-macrophage colony stimulating factor (GM-CSF), PI3 kinase/Akt signaling was mis-regulated as well. Our preliminary data strongly implicate a critical role for Shp2 in HSC maintenance and hematopoiesis, and Shp2 may have differential function in various types of hematopoietic cells and/or at different hematopoietic stage. Our central hypotheses are: 1) Shp2 is essential for the self-renewal and/or multiple lineage differentiation of HSC; 2) Shp2 is required for myelopoiesis, myelomonocytic cell proliferation and differentiation. We intend to fill the following knowledge gaps: 1) Is the defective hematopoiesis due to Shp2 deficiency HSC autonomous? 2) If so, what's the role of Shp2 in HSC? Does Shp2 play a role for HSC self-renewal, survival, and/or multiple lineage differentiation? 3) What is the primary signaling pathway(s) by which Shp2 regulates HSC properties? 4) Does the defective Ras/Erk and PI3 kinase/Akt signaling in Shp2 deficient myeloid cells account for their retarded growth, and affect their differentiation? Elucidating the molecular and cellular mechanism through which Shp2 modulates HSC self-renewal and multi-lineage differentiation will provide insights into mobilizing HSC for regenerative medicine and understanding how Shp2 mutations cause human hematopoietic diseases, such as juvenile myelomonocytic leukemia1 (JMML) and myeloid proliferative disorders (MPD).

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。 这项研究的长期目标是阐明正常造血和造血性疾病中蛋白质酪氨酸磷酸酶的功能。我们将重点关注含有蛋白质酪氨酸磷酸酶SHP2（PTPN11）的SRC同源性2（SH2）结构域的作用，该域基于我们从造血细胞/阶段特异性SHP2缺陷小鼠收集的最新数据。我们先前通过“ CRE-LOXP”系统在造血细胞中诱导SHP2的诱导缺失产生了PTPN11诱发的等位基因，导致骨髓呈植物，造血干细胞（HSC）的大幅降低，并降低了髓样和红细胞和核层和红细胞的菌落形成。 SHP2突变小鼠显得较小，不健康且严重贫血。 相反，由于粒细胞（G） - 巨噬细胞（M）祖细胞（GMP）阶段，缺乏SHP2表达的小鼠看起来正常，但随着年龄的增长而出现骨腹病。 这些突变小鼠的骨髓细胞显示CFU-M和CFU-GM菌落的数量和大小减少。 缺乏SHP2表达的骨髓衍生的巨噬细胞（BMM）表现出较低的生长和有缺陷的RAS/ERK激活，响应于巨噬细胞 - 颜色刺激因子（M-CSF）和粒细胞巨噬细胞刺激菌落刺激因子（GM-CSF），PI3激酶/AKT信号均为误解。 我们的初步数据强烈暗示SHP2在HSC维持和造血中的关键作用，而SHP2在各种类型的造血细胞和/或不同造血阶段可能具有不同的功能。我们的中心假设是：1）SHP2对于HSC的自我更新和/或多个谱系分化至关重要； 2）骨髓骨气，脊髓细胞细胞的增殖和分化需要SHP2。 我们打算填补以下知识差距：1）由于SHP2缺乏HSC自治而导致的造血缺陷吗？ 2）如果是这样，SHP2在HSC中的作用是什么？ SHP2在HSC自我更新，生存和/或多个谱系分化中是否起作用？ 3）SHP2调节HSC性质的主要信号通路是什么？ 4）SHP2中缺陷的RAS/ERK和PI3激酶/AKT信号是否会导致其迟滞的生长并影响其分化？阐明SHP2调节HSC自我更新和多轮差的分子和细胞机制将提供动员HSC的洞察力，以使HSC用于再生医学，并了解SHP2突变如何引起人类血肿性疾病，例如少量骨髓细胞性白细胞症（例如，jmmia1（Jmml）和myeloidereroider（myper）。