Probing the Role of the LRRK2 GTPase in Parkinson's Disease
探讨 LRRK2 GTPase 在帕金森病中的作用
基本信息
- 批准号:10642824
- 负责人:
- 金额:$ 2.99万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-06-01 至 2023-12-31
- 项目状态:已结题
- 来源:
- 关键词:AgeAllosteric SiteBindingBinding SitesBiochemicalBiological AssayBiologyBiophysicsCatalytic DomainCell LineCellsChemicalsClinicalCollaborationsDataDevelopmentDiseaseDopaminergic CellDoseEngineeringExhibitsFamilyFellowshipFunctional disorderFutureGTP BindingGeneticGenetic DeterminismGoalsGuanosineGuanosine TriphosphateGuanosine Triphosphate PhosphohydrolasesHigh PrevalenceHuman Genome ProjectHyperactivityIdiopathic Parkinson DiseaseLRRK2 geneLeucine-Rich RepeatLibrariesMass Spectrum AnalysisMeasuresMediatingMethodsModalityMolecularMolecular ConformationMutationNatureNerve DegenerationNeurodegenerative DisordersNorth AfricanNucleotidesOther GeneticsOutputParkinson DiseasePathogenesisPatientsPenetrancePhosphotransferasesPhysiologicalPhysiologyPositioning AttributePreclinical TestingPreventionProbabilityRecombinantsRisk FactorsRoleRouteScanningSecondary toSiteSymptomsSystemTechniquesTestingTherapeuticTherapeutically TargetableToxic effectTrainingWorkalpha synucleinautosomal dominant mutationbiophysical techniqueschemical geneticscohortdopaminergic neuroneffective therapyexperimental studygenetic approachgenetic associationgenome wide association studyimprovedin vivoinduced pluripotent stem cellinhibitorinsightkinase inhibitormutantneurotoxicitynovelresearch clinical testingscreeningsmall moleculesmall molecule inhibitorsuccesstargeted treatmenttherapeutic targettooltool development
项目摘要
Project Summary/Abstract
Parkinson’s disease is a common neurodegenerative disorder that has been described clinically for at least
200 years. While treatments have advanced to manage patient symptoms, a fundamental understanding of its
physiological underpinnings remains elusive, and no curative or progression modifying treatment is currently
available. Since the completion of the Human Genome Project, LRRK2 (Leucine Rich Repeat Kinase 2) has
been understood to form a strong genetic association with certain familial cases of Parkinson’s disease.
Autosomal dominant mutations in LRRK2 of variable penetrance have been demonstrated in isolated cohorts,
and GWAS studies have indicated the importance of LRRK2 SNPs in the development of idiopathic
Parkinson’s disease as well. Thus, the study of LRRK2 could elucidate findings in the pathophysiological
mechanisms of Parkinson’s as a whole. Current hypotheses postulate that LRRK2 kinase hyperactivity is
responsible for specific cellular toxicity and resultant neurodegeneration, resulting in the development of
LRRK2 kinase inhibitors in clinical and pre-clinical testing. One of the key catalytic domains of LRRK2, its Roc-
COR family GTPase, is a site of autosomal dominant mutations of high penetrance that also demonstrate
increased kinase activity. Despite this, this domain is relatively understudied compared to the kinase domain.
Efforts to understand the GTPase domain of LRRK2 may lead to an alternative modality of therapy, as there
are concerns about toxicity mechanisms in currently tested kinase inhibitors. I propose to study the LRRK2
GTPase using chemical genetic and chemical methods via the development of tool compounds and
appropriate biochemical and biophysical assays to determine the effect of GTPase modulation on LRRK2
mediated physiology. Preliminary data indicates that the LRRK2 GTPase is surveyable using a variety of
developed assay techniques, and can be recombinantly expressed in sufficient amounts to enable large scale
screening campaigns. In Aim 1, I propose to study the LRRK2 GTPase via the development of an electrophile
sensitive (ES) approach to conformationally lock the domain into either GDP- or GTP-bound states. I will then
introduce this system into iPSC-derived dopaminergic neurons and measure the effects of G nucleotide on
LRRK2 activity and localization. In Aim 2, I propose to execute complementary small molecule discovery
campaigns against the LRRK2 GTPase to uncover tool compounds that can target either the orthosteric or
disease mutation defined allosteric sites. I will then test these compounds in primary dopaminergic neuron cells
for their effects on ameliorating LRRK2 mutant-mediated cellular toxicity. Ultimately, the findings from these
studies will result in small molecule tool compounds and potential therapeutic leads that can be used to better
understand the molecular basis of Parkinson’s disease and its avenues for treatment. Training under this
fellowship will be supported by several collaborations including the Small Molecule Discovery center (SMDC)
at UCSF.
项目总结/文摘
项目成果
期刊论文数量(0)
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{{ truncateString('Lawrence Yang Zhu', 18)}}的其他基金
Probing the Role of the LRRK2 GTPase in Parkinson's Disease
探讨 LRRK2 GTPase 在帕金森病中的作用
- 批准号:
10412970 - 财政年份:2021
- 资助金额:
$ 2.99万 - 项目类别:
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