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:
- 金额:$ 32.23万
- 依托单位:
- 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:
- 关键词:AcidsActinsAlbers-Schonberg diseaseAnimal ModelAntibodiesAppearanceBindingBiologicalBiological AssayBone MatrixBone ResorptionBone necrosisBrainCRISPR/Cas technologyChloride ChannelsComplexConsensus SequenceCoupledCytoplasmCytoskeletonDataDevelopmentDiffusionDockingDrug TargetingEnzymesExhibitsExocytosisF-ActinFemoral FracturesForteoFunctional disorderFutureGenderGene ModifiedGene MutationGeneticGoalsGrantHomeostasisIdeal 1ImpairmentIn VitroIntegral Membrane ProteinJawKinesinKnock-outKnockout MiceLAMP-2LeadLeucine-Rich RepeatLysosomesMeasuresMediatingMolecularMonitorMotorMovementMusMutant Strains MiceMutationOsteoclastsOsteogenesisOsteoporosisOvariectomyPatientsPeptidesPeripheralPharmaceutical PreparationsPharmacotherapyPhenotypePhosphorylationPhosphorylation SitePhosphotransferasesPlayPostmenopauseProcessProtein-Serine-Threonine KinasesProteinsProteomicsProtonsPublic HealthRegulationResistanceRiskRoleSerineSerine/Threonine PhosphorylationSignal TransductionTNFSF11 geneTherapeuticThreonineTissuesTubular formationVariantWild Type MouseWomanWorkbisphosphonatebonebone fracture repairbone turnovercathepsin Kexperimental studyextracellularimprovedin vivoinhibitorknockout genelive cell imagingmimeticsmutantnovelosteoporosis with pathological fractureoverexpressionprotein complexresponsesmall molecule inhibitorspine bone structuretherapeutic developmentvacuolar 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
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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{{ truncateString('Weirong Xing', 18)}}的其他基金
Molecular Mechanisms of LRRK1 Regulation of Bone Homeostasis
LRRK1调节骨稳态的分子机制
- 批准号:
10363250 - 财政年份:2022
- 资助金额:
$ 32.23万 - 项目类别:
Mechanisms of Lrrk1 Regulation of Osteoclast Function
Lrrk1 调节破骨细胞功能的机制
- 批准号:
8769087 - 财政年份:2014
- 资助金额:
$ 32.23万 - 项目类别:
Regulation of Bone Formation by Ephrin B1 Signaling Pathways
Ephrin B1 信号通路对骨形成的调节
- 批准号:
8051630 - 财政年份:2010
- 资助金额:
$ 32.23万 - 项目类别:
Regulation of Bone Formation by Ephrin B1 Signaling Pathways
Ephrin B1 信号通路对骨形成的调节
- 批准号:
7896362 - 财政年份:2010
- 资助金额:
$ 32.23万 - 项目类别:
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