A Novel Genome-Wide Screen to Identify and Characterize Regulators of ALS Disease Modifier Gene Ataxin-2
一种新型全基因组筛选,用于识别和表征 ALS 疾病修饰基因 Ataxin-2 的调节因子
基本信息
- 批准号:10382981
- 负责人:
- 金额:$ 4.68万
- 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:2022-01-03 至 2023-01-02
- 项目状态:已结题
- 来源:
- 关键词:ALS patientsAction PotentialsAlzheimer&aposs DiseaseAmyotrophic Lateral SclerosisAntisense OligonucleotidesAutophagocytosisBehaviorBiogenesisBiologicalBiological ModelsBlood - brain barrier anatomyBrainCRISPR screenCRISPR/Cas technologyCell modelCellsClinicalClinical TrialsDNA-Binding ProteinsDataDepositionDevelopmentDiseaseDoseDrosophila genusDrug TargetingEnhancersEnzymesFDA approvedFRAP1 geneFluorescence-Activated Cell SortingFutureGene TargetingGenesGeneticGoalsHealthHumanIn VitroIndividualInduced pluripotent stem cell derived neuronsInheritedKnock-outLY6E geneLeadLengthLightLongevityLysosomesMammalian CellMediatingMessenger RNAMethodsModelingMotor NeuronsMusMuscleNatureNeurodegenerative DisordersNeuronsParkinson DiseasePathogenesisPathologicPathologyPathway interactionsPatientsPharmaceutical PreparationsPharmacologyPhysiologicalProtein OverexpressionProteinsRegulationRoleSCA2 proteinSafetySignal TransductionSpinalSpinal CordSystemTestingTherapeuticTherapeutic InterventionToxic effectWritingYeastsalpha synucleinamyotrophic lateral sclerosis therapybasecohortdeletion librarydisease phenotypedisorder riskdruggable targetflygenetic approachgenetic risk factorgenome wide screengenome-widein vivoinsightknock-downlifetime riskmotor deficitmotor impairmentmouse modelmulticatalytic endopeptidase complexneuron lossnew therapeutic targetnoveloverexpressionpolyglutamineprotein aggregationprotein complexprotein degradationrisk variantscreeningsmall moleculesmall molecule inhibitorsporadic amyotrophic lateral sclerosistau Proteinstherapeutic targetvacuolar H+-ATPase
项目摘要
Project Summary / Abstract
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder with an estimated lifetime risk of 1 in
400 individuals. ALS is clinically characterized by motor deficits, and pathologically by the selective loss of motor
neurons in the brain and spinal cord, as well as deposition of ubiquitinated proteinaceous aggregates of TDP-
43. Despite the presence of TDP-43 pathology in nearly all (~97%) brains of ALS patients, the genetic
underpinnings of the disease is highly heterogeneous, with ~90% being considered to be ‘sporadic,’ or having
no known genetic cause. The variable nature of the underlying causes has made treatment of the disease
historically difficult due to a lack of clear therapeutic targets. In the past decade, Ataxin-2 (ATXN2) has emerged
as a promising therapeutic target for ALS, as a potent genetic modifier of TDP-43 aggregation and toxicity across
multiple models of TDP-43 proteinopathy. Most excitingly, decreasing ATXN2 levels using anti-sense
oligonucleotides (ASOs) in a mouse model of TDP-43 overexpression led to a marked rescue of motor
impairments and dramatic extension of lifespan. Despite the promise of ASOs, having an orthogonal method to
reduce ATXN2 levels—such as a small molecule drug that can target one of its regulators—could have immense
practical benefit in the clinical context. Moreover, little remains known on how ATXN2 is normally regulated, as
well as its true role in disease. To gain mechanistic insight as well as to identify additional therapeutic targets, I
developed a novel FACS (fluorescence activated cell sorting)-based CRISPR/Cas9 genome-wide knockout
screening strategy. The idea was to identify suppressors and enhancers of ATXN2 protein levels in a reliable
and efficient way; genes that decrease ATXN2 levels upon knockout could serve as novel therapeutic targets for
ALS, while those that increase ATXN2 levels upon knockout could potentially contribute to heightened risk for
the disease. The screen yielded a multitude of promising hits, with many acting in same biological pathways, or
sometimes encoding subunits of one protein complex. One example of this is the lysosomal vacuolar ATPase
(v-ATPase), for which genes encoding nearly every subunit were found to be significant suppressors of ATXN2
protein levels in my screens. In addition to validating hits from the initial screens across multiple disease relevant
systems—such as in mouse primary neurons and human iPSC-derived neurons—I will expand the analysis to
delve deeper into the mechanism of how the v-ATPase is regulating ATXN2 protein levels. Moreover, given that
several FDA-approved small molecule drugs are available that inhibit v-ATPase subunits, I will test their safety
and efficacy in reducing ATXN2 levels and rescuing disease phenotypes in a mouse model of ALS in vivo. If this
approach is successful, there are a multitude of exciting possibilities for this screening platform and overall target
discovery approach that I believe could help to uncover regulators of many other neurodegenerative diseases
genes (e.g., tau and Ab in FTD and Alzheimer’s Disease, a-synuclein in Parkinson’s Disease) to empower the
discovery of novel therapeutic targets in contexts not limited to ALS.
项目摘要/摘要
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 }}
GARAM KIM其他文献
GARAM KIM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 }}
相似海外基金
Kilohertz volumetric imaging of neuronal action potentials in awake behaving mice
清醒行为小鼠神经元动作电位的千赫兹体积成像
- 批准号:
10515267 - 财政年份:2022
- 资助金额:
$ 4.68万 - 项目类别:
Signal processing in horizontal cells of the mammalian retina – coding of visual information by calcium and sodium action potentials
哺乳动物视网膜水平细胞的信号处理 â 通过钙和钠动作电位编码视觉信息
- 批准号:
422915148 - 财政年份:2019
- 资助金额:
$ 4.68万 - 项目类别:
Research Grants
CAREER: Resolving action potentials and high-density neural signals from the surface of the brain
职业:解析来自大脑表面的动作电位和高密度神经信号
- 批准号:
1752274 - 财政年份:2018
- 资助金额:
$ 4.68万 - 项目类别:
Continuing Grant
Development of Nanosheet-Based Wireless Probes for Multi-Simultaneous Monitoring of Action Potentials and Neurotransmitters
开发基于纳米片的无线探针,用于同时监测动作电位和神经递质
- 批准号:
18H03539 - 财政年份:2018
- 资助金额:
$ 4.68万 - 项目类别:
Grant-in-Aid for Scientific Research (B)
Population Imaging of Action Potentials by Novel Two-Photon Microscopes and Genetically Encoded Voltage Indicators
通过新型双光子显微镜和基因编码电压指示器对动作电位进行群体成像
- 批准号:
9588470 - 财政年份:2018
- 资助金额:
$ 4.68万 - 项目类别:
Enhanced quantitative imaging of compound action potentials in multi-fascicular peripheral nerve with fast neural Electrical Impedance Tomography enabled by 3D multi-plane softening bioelectronics
通过 3D 多平面软化生物电子学实现快速神经电阻抗断层扫描,增强多束周围神经复合动作电位的定量成像
- 批准号:
10009724 - 财政年份:2018
- 资助金额:
$ 4.68万 - 项目类别:
Enhanced quantitative imaging of compound action potentials in multi-fascicular peripheral nerve with fast neural Electrical Impedance Tomography enabled by 3D multi-plane softening bioelectronics
通过 3D 多平面软化生物电子学实现快速神经电阻抗断层扫描,增强多束周围神经复合动作电位的定量成像
- 批准号:
10467225 - 财政年份:2018
- 资助金额:
$ 4.68万 - 项目类别:
Fast high-resolution deep photoacoustic tomography of action potentials in brains
大脑动作电位的快速高分辨率深度光声断层扫描
- 批准号:
9423398 - 财政年份:2017
- 资助金额:
$ 4.68万 - 项目类别:
Noval regulatory mechanisms of axonal action potentials
轴突动作电位的新调节机制
- 批准号:
16K07006 - 财政年份:2016
- 资助金额:
$ 4.68万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
NeuroGrid: a scalable system for large-scale recording of action potentials from the brain surface
NeuroGrid:用于大规模记录大脑表面动作电位的可扩展系统
- 批准号:
9357409 - 财政年份:2016
- 资助金额:
$ 4.68万 - 项目类别: