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

这个子项目是许多利用 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。 破骨细胞是唯一负责骨吸收的细胞。 控制它们的数量和功能可以减少衰老过程中的骨矿物质损失，从而治疗骨质疏松症和其他影响大量美国人的骨退行性疾病。 这项提案的长期目标是阐明蛋白酪氨酸磷酸酶（PTP），特别是PTP Shp 2在破骨细胞生成和骨重建中的功能。 采用组织/细胞特异性基因敲除的方法，将Shp 2 floxed等位基因分别与LysM-Cre和Ctsk-Cre转基因系杂交，获得了破骨细胞前体细胞（OCP）和成熟破骨细胞中特异性表达Shp 2的小鼠。有了这些独特的小鼠模型和它们的细胞衍生物，我将能够解决三个重要的问题：目的1：确定Shp 2如何支持破骨细胞前体细胞的存活及其向功能性破骨细胞的增殖和分化;目的2：确定破骨细胞特异性Shp 2缺陷小鼠中的骨硬化表型是否由破骨细胞数量和/或功能的减少引起;目标3：确定巨噬细胞集落刺激因子（M-CSF）和核因子kB配体受体激活因子（RANKL）诱导的信号传导如何受Shp 2调节，以促进破骨细胞生成和破骨细胞吸收功能。详细了解这种分子机制将为设计新的治疗方法提供见解，用于治疗与衰老相关的骨退行性疾病，这些疾病没有恢复或再生治疗。

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.