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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：
10544742
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/10544742
关键词：
Acids Actins Albers-Schonberg disease Animal Model Antibodies Appearance Binding Biological Biological Assay Bone Matrix Bone Resorption Bone necrosis Brain CRISPR/Cas technology Chloride Channels Complex Consensus Sequence Coupled Cytoplasm Cytoskeleton Data Development Diffusion Docking Drug Targeting Enzymes Exhibits Exocytosis F-Actin Femoral Fractures Forteo Functional disorder Future Gender Gene Modified Gene Mutation Genetic Goals Grant Homeostasis Ideal 1 Impairment In Vitro Integral Membrane Protein Jaw 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 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 mimetics 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.

项目总结/摘要富含亮氨酸重复序列激酶1（Leucine rich repeat kinase 1，LRRK 1）是一种新的丝氨酸/苏氨酸激酶，在骨、脑等组织中表达。我们最近证明，Lrrk 1基因敲除（KO）小鼠以及Lrrk 1基因突变的患者，由于破骨细胞功能障碍和长骨和椎骨中骨吸收减少而导致的严重骨硬化症。更重要的是，Lrrk 1基因敲除小鼠具有终生的骨积累，并且对以下物质的合成代谢作用反应正常：但对卵巢切除术（OVX）诱导的骨凸有抗性。这些观察使LRRK 1 是治疗骨质疏松症的新型抗骨吸收药物的理想靶点。在这一补助金，我们的重点是执行在研究LRRK 1介导的石骨症特异性跨膜蛋白磷酸化作用的体内和体外研究蛋白1（OSTM 1）在氯离子通道7（CLC 7）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LRRK 1磷酸化可能是由于LRRK 1磷酸化导致的。位于苏氨酸328和丝氨酸329残基的OSTM 1通过稳定骨形成来调节OC功能和骨吸收。 OSTM 1/CLC 7复合物和促进溶酶体外周运动和溶酶体酸分泌到腔隙中 in vivo.这项拨款中提出的四年研究将提供LRRK 1磷酸化苏氨酸和丝氨酸的作用 OSTM 1残基在体内外骨吸收调节中的作用。这项申请的结果将有助于我们的了解LRRK 1和OSTM 1在破骨细胞中作用的分子机制，并开发潜在的抑制剂 LRRK 1在骨质疏松症治疗中的应用前景