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

描述（申请人提供）：骨质疏松症是一种主要的公共卫生问题，其特征是骨量和骨矿物质密度降低。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作用的分子机制。我们假设，在成骨细胞中，1）Wnt信号调节mTOR（雷帕霉素靶蛋白的哺乳动物同系物）活性，这是一种在调节蛋白质合成和细胞生长中起核心作用的必需丝氨酸/苏氨酸激酶; 2）mTOR在介导Wnt对骨的合成代谢作用中起关键作用。这些假设基于：1）我们的生物化学分析已经证明Wnt信号传导途径在体内和体外调节非成骨细胞中的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）两者的特征在于骨骼和颅面骨中的成骨细胞和成骨细胞改变，因此两者都被归类为硬化性骨发育不良;在这两种疾病中，分别涉及Wnt和mTOR信号传导的过度活跃。这两种疾病相似的临床和病理组织学特征表明Wnt和mTOR信号传导之间可能存在功能联系。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）揭示Wnt信号传导对骨的合成代谢作用的分子机制的关键见解，2）为硬化性骨发育不良的两种亚型（即HBM和TSC骨病变）共享的相似临床和病理组织学特征提供逻辑解释，以及3）涉及雷帕霉素，一种特异性mTOR抑制剂，以及其衍生物在治疗由过度活跃的Wnt信号传导引起的硬化性骨疾病中的用途。

DESCRIPTION (provided by applicant): 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 Aims are: 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.