Molecular Mechanisms of LRRK1 Regulation of Bone Homeostasis

项目摘要/摘要 亮氨酸富含重复蛋白1(LRRK1)是一种新的丝氨酸/苏氨酸激酶，在骨骼、脑等组织中均有表达。 我们最近证明了Lrrk1基因敲除(KO)小鼠和一名Lrrk1基因突变的患者是 由于长骨和椎骨中破骨细胞功能障碍和骨吸收减少而导致的严重的骨质疏松。更多 重要的是，Lrrk1 KO小鼠终生有骨积累，并对合成代谢作用做出正常反应 但对卵巢切除(OVX)诱导的骨BOSS耐药。这些观察使LRRK1 治疗骨质疏松症的新型抗吸收药物的理想靶点。在这笔赠款中，我们的重点是在 LRRK1介导的骨化症特异性跨膜磷酸化作用的体内和体外研究 蛋白1(OSTM1)在调节氯离子通道7(CLC7)复合体稳定、溶酶体外周的作用 运动、溶酶体酸分泌和OC功能。为此，我们假设LRRK1的磷酸化 苏氨酸328和丝氨酸329残基上的OSTM1通过稳定骨吸收调节OC功能和骨吸收 OSTM1/CLC7复合体促进溶酶体周向运动和溶酶体酸分泌进入腔隙 在活体内。这笔赠款提议的为期四年的研究将提供苏氨酸和丝氨酸的LRRK1磷酸化作用。 OSTM1在体内外调节骨吸收中的残留物。这个应用程序的结果将帮助我们的 了解LRRK1和OSTM1在破骨细胞中作用的分子机制及开发潜在的抑制剂 LRRK1用于治疗骨质疏松症。

Project Summary/Abstract Leucine rich repeat kinase 1 (LRRK1), a novel serine/threonine kinase, is expressed in bones, brain and other tissues. We recently demonstrated that Lrrk1 gene knockout (KO) mice as well as a patient with a Lrrk1 gene mutation are severely osteopetrotic due to osteoclast dysfunction and reduced bone resorption in long and vertebra bones. More importantly, Lrrk1 KO mice had lifelong bone accumulation and responded normally to the anabolic actions of teriparatide treatment but were resistant to ovariectomy (OVX)-induced bone boss. These observations make LRRK1 an ideal target of a novel anti-resorption drugs for treatment of osteoporosis. In this grant, our focus is to perform in vivo and in vitro studies to study the role of LRRK1-mediated phosphorylation of osteopetrosis specific transmembrane protein 1 (OSTM1) in the regulation of chloride channel 7 (CLC7) complex stabilization, lysosomal peripheral movement, lysosomal acid secretion and OC function. To this end, we hypothesize that LRRK1 phosphorylation of OSTM1 at residues of threonine 328 and serine 329 regulates OC function and bone resorption by stabilization of OSTM1/CLC7 complex and promotion of lysosomal peripheral movement and lysosomal acid secretion into lacuna in vivo. Four-year studies proposed in this grant will deliver the role of LRRK1 phosphorylation of threonine and serine residues of OSTM1 in regulation of bone resorption in vitro and in vivo. The results of this application will help our understanding of molecular mechanisms of LRRK1 and OSTM1 actions in osteoclast and develop potential inhibitors of LRRK1 for treatment of osteoporosis in future.