Shp2 in Osteoclastogenesis and Bone Remodeling

Shp2 在破骨细胞生成和骨重塑中的作用

基本信息

批准号：
7944160
负责人：
Wentian Yang
金额：
$ 17.21万
依托单位：
RHODE ISLAND HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-30 至 2012-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7944160
关键词：
Address Adherence Affect Age Albers-Schonberg disease Alleles American Animals Architecture Biochemical Biological Biological Assay Bone Density Bone Development Bone Marrow Bone Marrow Cells Bone Matrix Bone Resorption Bone remodeling Breeding Cells Colony-forming units Data Defect Degenerative Disorder Deposition Development Diagnostic radiologic examination Disease Generations Goals Growth Hematopoietic Histology Homeostasis In Vitro Lead Ligands Macrophage Colony-Stimulating Factor Macrophage Colony-Stimulating Factor Receptor Maintenance Marrow Menopause Mesenchymal Stem Cells Minerals Molecular Molecular Target Mus Mutant Strains Mice Mutation Nuclear Osteoblasts Osteoclasts Osteoporosis PTPN11 gene Pharmaceutical Preparations Phenotype Play Positioning Attribute Protein Tyrosine Phosphatase Regulation Research Role Signal Transduction Skeletal Development Src homology 2 domain-containing, transforming protein 1 Staining method Stains Surface System Thick Tissues Transgenic Organisms United States Woman age related bone bone mass c-fms Proto-Oncogenes cell type design in vivo insight knockout gene macrophage migration mouse model mutant novel novel therapeutics osteoclastogenesis public health relevance receptor regenerative response skeletal skeletal disorder stem tartrate-resistant acid phosphatase

项目摘要

DESCRIPTION (provided by applicant): 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 and mature osteoclasts. My preliminary data demonstrate that mice lacking Shp2 in osteoclasts are osteopetrotic, and bone marrow cells from the mutant mice have impaired osteoclastogenesis ex vivo, implicating a critical role for Shp2 in osteoclast development, bone remodeling and mineral maintenance. With these unique mouse models and their cellular derivatives, I will be in an unique 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 bone 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. PUBLIC HEALTH RELEVANCE: We will study the role of protein tyrosine phosphatase Shp2 in osteoclastogenesis and osteoclast functional activation. Our research will lead to a better understanding of the moceluar and cellular mechanism of Shp2 in osteoclast development and functional regulation, and identifying potential novel targets for treating osteoporosis and other bone degenerative diseases.

描述（由申请人提供）：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，以产生在破骨细胞前体和成熟的骨细胞中缺乏SHP2表达的小鼠。我的初步数据表明，在破骨细胞中缺乏SHP2的小鼠是骨质原的，而来自突变小鼠的骨髓细胞却损害了破骨细胞生成的发生，这意味着SHP2在骨细胞发育，骨重塑和矿物质维持中对SHP2的关键作用。借助这些独特的小鼠模型及其细胞衍生物，我将处于一个独特的位置，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生存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；目的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，该信号受到SHP2调控的核因子Kb配体（RANKL），以用于破骨细胞造成的破裂性塑料和破骨细胞生成作用。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。公共卫生相关性：我们将研究蛋白质酪氨酸磷酸酶SHP2在破骨细胞生成和破骨细胞功能激活中的作用。我们的研究将使对破骨细胞发育和功能调节中SHP2的moceluar和细胞机制有了更好的了解，并确定了治疗骨质疏松症和其他骨变性疾病的潜在新靶标。