PILOT 1: PROTEIN TYROSINE PHOSPHATASE SHP2 IN OSTEOCLASTOGENESIS/BONE REMODEL

试点 1：蛋白质酪氨酸磷酸酶 SHP2 在破骨细胞生成/骨重塑中的作用

• 批准号: 7959908
• 负责人: Wentian Yang
• 金额: $ 5.09万
• 依托单位: RHODE ISLAND HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-01 至 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7959908
• 关键词: Address; Affect; Age; Alleles; American; Bone Resorption; Bone remodeling; Breeding; Cells; Centers of Research Excellence; Computer Retrieval of Information on Scientific Projects Database; Degenerative Disorder; Funding; Goals; Grant; Health; Institution; Ligands; Macrophage Colony-Stimulating Factor Receptor; Minerals; Molecular; Mus; Nuclear; Osteoclasts; Osteoporosis; PTPN11 gene; Phenotype; Positioning Attribute; Protein Tyrosine Phosphatase; Research; Research Personnel; Resources; Signal Transduction; Source; Tissues; Transgenic Organisms; United States National Institutes of Health; age related; bone; design; insight; knockout gene; mouse model; novel therapeutics; osteoclastogenesis; regenerative; repaired; skeletal; Address; Affect; Age; Alleles; American; Bone Resorption; Bone remodeling; Breeding; Cells; Centers of Research Excellence; Computer Retrieval of Information on Scientific Projects Database; Degenerative Disorder; Funding; Goals; Grant; Health; Institution; Ligands; Macrophage Colony-Stimulating Factor Receptor; Minerals; Molecular; Mus; Nuclear; Osteoclasts; Osteoporosis; PTPN11 gene; Phenotype; Positioning Attribute; Protein Tyrosine Phosphatase; Research; Research Personnel; Resources; Signal Transduction; Source; Tissues; Transgenic Organisms; United States National Institutes of Health; age related; bone; design; insight; knockout gene; mouse model; novel therapeutics; osteoclastogenesis; regenerative; repaired; skeletal

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. Osteoclasts are the exclusive cells responsible for bone resorption. Governing their number and function can reduce bone mineral loss during ageing, and therefore treat osteoporosis and other bone degenerative diseases that affect a significant number of Americans. The long-term goal of this proposal is to elucidate the function of protein tyrosine phosphatases (PTP), specifically PTP Shp2, in osteoclastogenesis and bone remodeling. Taking a tissue/cell specific gene knockout approach, I bred Shp2 floxed allele with LysM-Cre and Ctsk-Cre transgenic lines respectively to generate mice lacking Shp2 expression specifically in osteoclast precursors (OCP) and mature osteoclasts. With these unique mouse models and their cellular derivatives, I will be in a position to address three important questions: Aim 1: to determine how Shp2 supports the survival of osteoclast precursors and their proliferation and differentiation towards functional osteoclasts; Aim 2: to determine whether the osteopetrotic phenotype in osteoclast-specific Shp2 deficient mice is caused by reduction of osteoclast numbers, and/or function; Aim 3: to define how is the signaling evoked by macrophage-colony stimulating factor (M-CSF) and receptor activator of nuclear factor kB ligand (RANKL) regulated by Shp2 for osteoclastogenesis and osteoclast resorptive function. Understanding this molecular machinery in detail will provide insights into designing new therapeutics for ageing related bone degenerative diseases for which there are no restorative or regenerative treatment.

该副本是利用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这不一定是调查员的机构。 破骨细胞是负责骨吸收的独家细胞。 管理其数量和功能可以减少衰老期间的骨矿物质损失，因此治疗骨质疏松症和其他影响大量美国人的骨变性疾病。 该提案的长期目标是阐明蛋白质酪氨酸磷酸酶（PTP），特别是PTP SHP2的功能，在破骨细胞生成和骨骼重塑中的功能。 我以组织/细胞的特异性基因敲除方法，分别用lysm-cre和ctsk-cre转基因线饲养了SHP2等位基因，以生成在破骨细胞前体（OCP）和成熟的骨细胞中缺乏SHP2表达的小鼠。借助这些独特的小鼠模型及其细胞衍生物，我将可以解决三个重要问题：目标1：确定SHP2如何支持破骨细胞前体的存活以及它们对功能性破骨细胞的增殖和分化； AIM 2：确定破骨细胞特异性SHP2缺乏小鼠中的骨质术表型是否是由破骨细胞数的减少和/或功能引起的；目标3：定义如何通过巨噬细胞刺激因子（M-CSF）和核因子KB配体的受体激活剂（RANKL）诱发的信号传导，该信号被SHP2调节的核因子KB配体（RANKL）用于破骨塑料和破骨细胞生成功能。详细了解这种分子机械将为设计新的治疗剂提供有关衰老相关的骨退行性疾病的新疗法，而这些疾病没有恢复性或再生治疗。