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: 8168498
• 负责人: Wentian Yang
• 金额: $ 21.11万
• 依托单位: RHODE ISLAND HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8168498
• 关键词: 1-Phosphatidylinositol 3-Kinase; Accounting; Adolescent; Affect; Alleles; Bone Marrow; Cell Maintenance; Cell Proliferation; Cells; Computer Retrieval of Information on Scientific Projects Database; Data; Development; Disease; Erythroid; Funding; Goals; Grant; Granulocyte-Macrophage Colony-Stimulating Factor; Growth; Hematopoiesis; Hematopoietic; Hematopoietic stem cells; Institution; Knowledge; Macrophage Colony-Stimulating Factor; Maintenance; Marrow; Molecular; Mus; Mutant Strains Mice; Mutation; Myelogenous; Myeloid Cells; Myelopoiesis; PTPN11 gene; Phosphoric Monoester Hydrolases; Play; Property; Protein Tyrosine Phosphatase; Regenerative Medicine; Research; Research Personnel; 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; design; granulocyte; human disease; insight; macrophage; novel therapeutic intervention; progenitor; response; self-renewal

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. 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 obtained from hematopoietic cell/stage-specific Shp2 deficient mice. We previously generated a Shp2 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. The 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 developmental 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 above 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, understanding how Shp2 mutations cause human diseases, such as juvenile myelomonocytic leukemia1 (JMML) and other myeloid proliferative disorders (MPD)2, and designing new therapeutic approaches

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 本研究的长期目标是阐明蛋白酪氨酸磷酸酶在正常造血和造血疾病中的功能。我们将专注于Src同源性2（SH 2）结构域包含蛋白酪氨酸磷酸酶Shp 2（PTPN 11）的作用，基于我们最近从造血细胞/阶段特异性Shp 2缺陷小鼠获得的数据。我们先前产生了Shp 2 floxed等位基因，通过“Cre-loxP”系统在造血细胞中诱导缺失Shp 2导致骨髓发育不全，造血干细胞（HSC）的大量减少以及髓系和红系的集落形成减少。突变小鼠看起来更小，不健康，严重贫血。 相比之下，自粒细胞（G）-巨噬细胞（M）祖细胞（GMP）阶段缺乏Shp 2表达的小鼠表现正常，但随着年龄的增长发展成骨质疏松症。 来自这些突变小鼠的骨髓细胞显示CFU-M和CFU-GM集落的数量和大小减少。 缺乏Shp 2表达的骨髓源性巨噬细胞（BMM）在巨噬细胞集落刺激因子（M-CSF）和粒细胞-巨噬细胞集落刺激因子（GM-CSF）的作用下表现出生长迟缓和Ras/Erk活化缺陷，PI 3激酶/Akt信号也被错误调节。 我们的初步数据强烈暗示了Shp 2在HSC维持和造血中的关键作用，并且Shp 2可能在各种类型的造血细胞和/或在不同发育阶段具有不同的功能。我们的中心假设是1）Shp 2对于HSC的自我更新和/或多谱系分化是必需的; 2）Shp 2对于骨髓生成、骨髓单核细胞增殖和分化是必需的。 我们打算填补以下知识空白：1）由于Shp 2缺陷HSC的造血缺陷是自主的吗？2)如果是这样，Shp 2在HSC中的作用是什么？Shp 2是否在HSC自我更新、存活和/或多谱系分化中发挥作用？3)Shp 2调节上述HSC特性的主要信号通路是什么？4)Ras/Erk和PI 3激酶/Akt信号通路的缺陷是否导致Shp 2缺陷型骨髓细胞生长迟缓并影响其分化？阐明Shp 2调节HSC自我更新和多谱系分化的分子和细胞机制将为动员HSC用于再生医学提供见解，了解Shp 2突变如何导致人类疾病，如青少年粒单核细胞白血病1（JMML）和其他骨髓增生性疾病（MPD）2，并设计新的治疗方法