Molecular Mechanisms of LRRK1 Regulation of Bone Homeostasis

LRRK1调节骨稳态的分子机制

基本信息

批准号：
10363250
负责人：
Weirong Xing
金额：
$ 32.23万
依托单位：
LOMA LINDA VETERANS ASSN RESEARCH & EDUC
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-01-01 至 2025-12-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10363250
关键词：
Acids Actins Albers-Schonberg disease Animal Model Antibodies Appearance Biological Biological Assay Bone Matrix Bone Resorption Bone necrosis Brain CRISPR/Cas technology Chloride Channels Complex Consensus Sequence Coupled Cytoplasm Cytoskeleton Data Development Diffuse Docking Drug Targeting Enzymes Exhibits Exocytosis F-Actin Femoral Fractures Forteo Functional disorder Future Gender Gene Mutation Gene-Modified Genetic Goals Grant Homeostasis Ideal 1 Impairment In Vitro Integral Membrane Protein Jaw K ATPase Kinesin Knock-out Knockout Mice LAMP-2 Lead Leucine-Rich Repeat Lysosomes Measures Mediating Molecular Monitor Motor Movement Mus Mutant Strains Mice Mutation Osteoclasts Osteogenesis Osteoporosis Ovariectomy Patients Peptides Peripheral Pharmaceutical Preparations Pharmacotherapy Phenotype Phosphorylation Phosphorylation Site Phosphotransferases Play Postmenopause Process Protein-Serine-Threonine Kinases Proteins Proteomics Protons Public Health Regulation Resistance Risk Role Serine Serine/Threonine Phosphorylation Signal Transduction TNFSF11 gene Therapeutic Threonine Time Tissues Tubular formation Variant Wild Type Mouse Woman Work bisphosphonate bone bone fracture repair bone turnover cathepsin K experimental study extracellular improved in vivo inhibitor knockout gene live cell imaging mutant novel osteoporosis with pathological fracture overexpression protein complex response small molecule inhibitor spine bone structure therapeutic development vacuolar H+-ATPase

项目摘要

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.

项目概要/摘要富含亮氨酸重复激酶 1 (LRRK1) 是一种新型丝氨酸/苏氨酸激酶，在骨骼、大脑和其他组织中表达。我们最近证明，Lrrk1 基因敲除 (KO) 小鼠以及具有 Lrrk1 基因突变的患者由于破骨细胞功能障碍和长骨和椎骨骨吸收减少而导致严重骨石化。更多的重要的是，Lrrk1 KO 小鼠具有终生骨积累，并且对合成代谢作用有正常反应。特立帕肽治疗，但对卵巢切除术（OVX）诱导的骨隆起有抵抗力。这些观察结果使 LRRK1 是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，我们的重点是执行体内和体外研究研究 LRRK1 介导的骨硬化特异性跨膜磷酸化的作用蛋白 1 (OSTM1) 在氯离子通道 7 (CLC7) 复合物稳定调节中的作用，溶酶体外周运动、溶酶体酸分泌和 OC 功能。为此，我们假设 LRRK1 磷酸化苏氨酸 328 和丝氨酸 329 残基上的 OSTM1 通过稳定 OSTM1/CLC7复合物与溶酶体外周运动和溶酶体酸向腔隙分泌的促进体内。此项资助中提出的为期四年的研究将揭示 LRRK1 苏氨酸和丝氨酸磷酸化的作用 OSTM1 残基在体外和体内骨吸收调节中的作用。该应用程序的结果将帮助我们了解 LRRK1 和 OSTM1 在破骨细胞中作用的分子机制并开发潜在的抑制剂 LRRK1未来用于治疗骨质疏松症。