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

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.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目及 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 中心，不一定是研究者的机构。 破骨细胞是负责骨吸收的唯一细胞。 控制它们的数量和功能可以减少衰老过程中骨矿物质的流失，从而治疗影响大量美国人的骨质疏松症和其他骨退行性疾病。 该提案的长期目标是阐明蛋白酪氨酸磷酸酶 (PTP)，特别是 PTP Shp2，在破骨细胞生成和骨重塑中的功能。 采用组织/细胞特异性基因敲除方法，我分别用 LysM-Cre 和 Ctsk-Cre 转基因品系培育 Shp2 floxed 等位基因，以产生在破骨细胞前体 (OCP) 和成熟破骨细胞中特异性缺乏 Shp2 表达的小鼠。凭借这些独特的小鼠模型及其细胞衍生物，我将能够解决三个重要问题： 目标 1：确定 Shp2 如何支持破骨细胞前体的存活及其增殖和分化为功能性破骨细胞；目标2：确定破骨细胞特异性Shp2缺陷小鼠的骨石化表型是否是由破骨细胞数量和/或功能减少引起的；目标 3：明确 Shp2 调节巨噬细胞集落刺激因子 (M-CSF) 和核因子 kB 配体受体激活剂 (RANKL) 引发的信号如何促进破骨细胞生成和破骨细胞再吸收功能。详细了解这种分子机制将为设计治疗与衰老相关的骨退行性疾病（目前尚无恢复或再生治疗方法）的新疗法提供见解。