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/摘要
帕金森氏病是一种常见的神经退行性疾病,至少在临床上已有描述。
两百年了虽然治疗方法已经发展到控制患者症状,但对其症状的基本理解仍然存在。
生理学基础仍然难以捉摸,并且目前没有治愈性或进展调节治疗。
available.自人类基因组计划完成以来,LRRK 2(富含亮氨酸重复激酶2)已被发现,
据了解,它与帕金森病的某些家族病例形成了强烈的遗传关联。
LRRK 2中可变突变率的常染色体显性突变已在孤立的队列中得到证实,
和GWAS研究表明LRRK 2 SNP在特发性阿尔茨海默病的发生中的重要性。
帕金森氏症也是。因此,LRRK 2的研究可以阐明在病理生理学方面的发现。
帕金森病的发病机制目前的假设假定LRRK 2激酶过度活跃是
负责特定的细胞毒性和由此产生的神经变性,导致发展
LRRK 2激酶抑制剂的临床和临床前测试。LRRK 2的关键催化结构域之一,其Roc-
COR家族GT3是一个常染色体显性高突变位点,
增加激酶活性。尽管如此,与激酶结构域相比,该结构域相对研究不足。
努力了解LRRK 2的GT3结构域可能会导致一种替代的治疗方式,
是目前测试的激酶抑制剂的毒性机制的关注。我建议研究LRRK 2
通过开发工具化合物,使用化学遗传学和化学方法进行GTcycle,
适当的生物化学和生物物理测定以确定GT3调节对LRRK 2的影响
介导生理学初步数据表明,LRRK 2 GTSTAY可以使用各种
开发的测定技术,并且可以以足够的量重组表达,
筛查活动。在目标1中,我建议通过开发亲电试剂来研究LRRK 2 GTdR
敏感(ES)的方法,以构象锁定到GDP或GTP结合状态的结构域。然后我将
将该系统引入iPSC衍生的多巴胺能神经元,并测量G核苷酸对
LRRK 2活性和定位。在目标2中,我建议执行互补小分子发现
针对LRRK 2 GTdR的运动,以发现可以靶向正构或
疾病突变定义的变构位点。然后我将在初级多巴胺能神经元细胞中测试这些化合物
因为它们对改善LRRK 2突变体介导的细胞毒性的作用。最终,这些发现
研究将产生小分子工具化合物和潜在的治疗先导物,可用于更好地
了解帕金森病的分子基础及其治疗途径。在此培训
该奖学金将得到包括小分子发现中心(SMDC)在内的几个合作项目的支持
在UCSF
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)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Lawrence Yang Zhu其他文献
Lawrence Yang Zhu的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ 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:
相似海外基金
Allosteric site prediction and transmission of functional residues with atomistic graph analysis
通过原子图分析进行功能残基的变构位点预测和传递
- 批准号:
2859072 - 财政年份:2020
- 资助金额:
$ 2.99万 - 项目类别:
Studentship
Creation of novei anticancer lead compounds targeting the allosteric site of c-Met kinase
创建针对 c-Met 激酶变构位点的新型抗癌先导化合物
- 批准号:
16K08327 - 财政年份:2016
- 资助金额:
$ 2.99万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Studying how a general allosteric site regulates protein kinase function
研究一般变构位点如何调节蛋白激酶功能
- 批准号:
8595027 - 财政年份:2013
- 资助金额:
$ 2.99万 - 项目类别:
Studying how a general allosteric site regulates protein kinase function
研究一般变构位点如何调节蛋白激酶功能
- 批准号:
8704718 - 财政年份:2013
- 资助金额:
$ 2.99万 - 项目类别:
Studying how a general allosteric site regulates protein kinase function
研究一般变构位点如何调节蛋白激酶功能
- 批准号:
8874171 - 财政年份:2013
- 资助金额:
$ 2.99万 - 项目类别:
STRUC DETERMINATION OF METAL-SUBSTITUTED & ALLOSTERIC SITE VARIANTS OF H INFLU
金属取代物的结构测定
- 批准号:
7955561 - 财政年份:2009
- 资助金额:
$ 2.99万 - 项目类别:
EXAMINATION OF ALLOSTERIC SITE OF SEROTONIN TRANSPORTER USING TRANSGENIC MICE
使用转基因小鼠检查血清素转运蛋白的变构位点
- 批准号:
7715783 - 财政年份:2008
- 资助金额:
$ 2.99万 - 项目类别:
STRUC DETERMINATION OF METAL-SUBSTITUTED & ALLOSTERIC SITE VARIANTS OF H INFLU
金属取代物的结构测定
- 批准号:
7721325 - 财政年份:2008
- 资助金额:
$ 2.99万 - 项目类别:
ALLOSTERIC SITE STRUCTURES OF CARDIOVASCULAR CHANNELS
心血管通道的变构位点结构
- 批准号:
7215384 - 财政年份:2007
- 资助金额:
$ 2.99万 - 项目类别:
EXAMINATION OF ALLOSTERIC SITE OF SEROTONIN TRANSPORTER USING TRANSGENIC MICE
使用转基因小鼠检查血清素转运蛋白的变构位点
- 批准号:
7562646 - 财政年份:2007
- 资助金额:
$ 2.99万 - 项目类别: