mTOR SIGNALING: A NOVEL MECHANISM OF WNT'S ANABOLIC EFFECTS ON BONE

mTOR 信号传导：WNT 对骨合成代谢影响的新机制

• 批准号: 7779480
• 负责人: Hongjiao Ouyang
• 金额: $ 34.4万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-03-15 至 2011-05-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7779480
• 关键词: Affect; Anabolic Agents; Biochemical; Biological; Biology; Bone Density; Bone Diseases; Bone Resorption; Cell Culture Techniques; Cell Differentiation process; Cell Proliferation; Cell Surface Receptors; Cells; Clinical; Clinical Data; Developmental Bone Diseases; Disease; Exhibits; Extracellular Matrix; Fracture; Genetic; Goals; Hereditary Disease; Homologous Gene; Human; Hyperactive behavior; In Vitro; Lesion; Mediating; Modality; Modeling; Molecular; Mus; Mutation; Operative Surgical Procedures; Osteoblasts; Osteogenesis; Osteoporosis; Osteosclerotic Lesion; Pathway interactions; Phenotype; Phosphorylation; Play; Protein Biosynthesis; Protein-Serine-Threonine Kinases; Proteins; Public Health; Recombinant Proteins; Research Personnel; Role; Sclerosis; Series; Signal Pathway; Signal Transduction; Signal Transduction Pathway; Sirolimus; Syndrome; TSC2 gene; Tuberous Sclerosis; Tuberous sclerosis protein complex; United States; Work; analog; base; bone; bone mass; cell growth; cell type; craniofacial; gain of function mutation; in vivo; inhibitor/antagonist; insight; mTOR protein; novel; novel therapeutics; postnatal; prevent; programs; skeletal; traditional therapy; transcription factor

Osteoporosis is a leading public health problem that is characterized by reduced bone mass and bone mineral density. Wnt signaling promotes postnatal bone mass accrual. Our long-term goal is to elucidate the molecular mechanisms underlying the anabolic effects of Wnt signaling pathway on bone. We hypothesize that, in osteoblasts, 1) Wnt signaling regulates mTOR (mammalian homolog of target of rapamycin) activity, an essential serine/threonine kinase that plays a central role in regulating protein synthesis and cell growth; and 2) mTOR plays a critical role in mediating Wnt's anabolic effects on bone. These hypotheses are based on: 1) our biochemical analyses have demonstrated that the Wnt signaling pathway regulates mTOR activity in non-osteoblasts both in vivo and in vitro; and 2) both autosomal dominant high bone mass disease (HBM) and tuberous sclerosing bone dysplasia (TSC) are featured by osteoblastic and osteosclerotic changes in skeletal and craniofacial bones, thus both having being classified to sclerosing bone dysplasia; in these two diseases, hyperactivity of Wnt and mTOR signaling are implicated, respectively. The similar clinical and pathohistological features of these two diseases suggest a possible functional linkage between Wnt and mTOR signaling. The Specific Aimsare: Aim 1: Determine whether Wnt signaling promotes mTOR activity in bone, both in vivo and in vitro. Aim 2: Elucidate the underlying mechanisms by which Wnt signaling regulates mTOR activity. Aim 3. Determine whether mTOR is required for Wnt anabolic effects on bone. ; Successful completion of these specific aims will 1) shed critical insight into the molecular mechanism of Wnt signaling' anabolic effects on bone, 2) provide a logical explanation for the similar clinical and pathohistological features shared by two subtypes of sclerosing bone dysplasias, i.e. HBM and TSC bone lesions, and 3) implicates rapamycin, a specific mTOR inhibitor, and the derivatives in treating sclerosing bone diseases caused by hyperactive Wnt signaling.

骨质疏松症是一个主要的公共卫生问题，其特征是骨量减少， 矿物密度Wnt信号促进出生后骨量增加。我们的长期目标是阐明 Wnt信号通路对骨合成代谢影响的分子机制。我们 假设在成骨细胞中，1）Wnt信号调节mTOR（哺乳动物同源物， 雷帕霉素）活性，一种在调节蛋白质中起核心作用的必需丝氨酸/苏氨酸激酶 合成和细胞生长;和2）mTOR在介导Wnt对骨的合成代谢作用中起关键作用。 这些假设是基于：1）我们的生化分析已经证明，Wnt信号传导 途径调节体内和体外非成骨细胞中的mTOR活性;和2）常染色体 显性高骨量疾病（HBM）和结节性硬化性骨发育不良（TSC）的特点是， 骨骼和颅面骨的成骨细胞和成骨细胞变化，因此两者都被归类为 硬化性骨发育不良;在这两种疾病中，涉及Wnt和mTOR信号传导的过度活跃， 分别这两种疾病相似的临床和病理组织学特征表明， Wnt和mTOR信号传导之间的功能性连接。具体目标是： 目的1：确定Wnt信号传导是否促进体内和体外骨中mTOR活性。 目的2：阐明Wnt信号调节mTOR活性的潜在机制。 目标3.确定mTOR是否是Wnt对骨的合成代谢作用所必需的。 ; 这些特定目标的成功完成将1）对Wnt的分子机制产生重要的见解 信号对骨的合成代谢作用，2）为类似的临床和 硬化性骨发育不良的两种亚型（即HBM和TSC骨）共有的病理组织学特征 损伤，和3）涉及雷帕霉素，一种特异性mTOR抑制剂，和治疗硬化的衍生物 由过度活跃的Wnt信号传导引起的骨疾病。