Exploring Mechanisms of Pathogenicity in C9ORF72 Frontotemporal Dementia and Amyotrophic Lateral Sclerosis
探索C9ORF72额颞叶痴呆和肌萎缩侧索硬化症的致病机制
基本信息
- 批准号:9750565
- 负责人:
- 金额:$ 10.85万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2018
- 资助国家:美国
- 起止时间:2018-08-01 至 2021-02-28
- 项目状态:已结题
- 来源:
- 关键词:AccountingAddressAffectAgeAmyotrophic Lateral SclerosisAnimal ModelAnimalsAnxietyAutoimmunityBehaviorBehavioralBiochemicalBiological ModelsBone MarrowBrainC9ORF72Cell LineCellsCerebrospinal FluidCessation of lifeChromosomes, Human, Pair 9CognitiveDevelopmentDiagnosisDipeptidesDiseaseDisease OutcomeEmotionalEnvironmental Risk FactorEnzyme-Linked Immunosorbent AssayEquilibriumEtiologyForelimbFrontotemporal DementiaFutureGene ExpressionGenesGeneticGoalsHand StrengthHumanImageImageryImmune systemIn VitroIndividualInflammationInflammatoryInitiator CodonIntronsKnock-outLeadLearningLinguisticsMeasurementMentorsMetabolismMethodologyMicrogliaModelingMolecularMotorMotor NeuronsMovementMusMuscleMuscle functionMutationNerve DegenerationNeurodegenerative DisordersNeurogliaNeuronal DysfunctionNeuronsNeurophysiology - biologic functionOnset of illnessOrganismOrthologous GeneOther GeneticsParalysedPathogenicityPathologyPathway interactionsPatientsPenetrancePeripheral NervesPharmacologyPhasePhenotypePlayPopulationPredispositionPrevention strategyProductionProgressive DiseaseProteinsRNARNA-Binding ProteinsReading FramesRegulationResearchResearch PersonnelRoleRunningSkeletal MuscleSocial InteractionSocietiesSpinalSpinal CordStressTNF geneTechnical ExpertiseTestingTherapeuticTissuesToll-like receptorsToxic effectTrainingTranscriptTranslatingUnited StatesVirusage related neurodegenerationbehavior testbehavioral studycell typefrontotemporal lobar dementia-amyotrophic lateral sclerosisgain of functiongene productglial activationimproved functioningin vitro Modelin vivoinduced pluripotent stem cellinsightloss of functionloss of function mutationmacrophagenerve supplynervous system disorderneuroinflammationneuromechanismneuromuscularneuron lossnovelpre-clinicalprotein aggregateprotein biomarkersrelating to nervous systemresponsesciatic nervescreeningtherapeutic candidatetherapy developmenttraffickingtrizolvector
项目摘要
Project Summary/Abstract
Age-related neurodegenerative disorders represent a major financial and emotional burden to society, but to date no
preventative strategies have been developed. Frontotemporal dementia (FTD) and Amyotrophic lateral sclerosis (ALS) are
relentlessly progressive diseases which involve the degeneration of neurons important for behavior and muscle movement,
respectively. A hexanucleotide repeat expansion in a non-protein-coding region of the gene C9ORF72 was recently
discovered to be the most common cause of FTD and ALS, responsible for 10% of all diagnoses. Two prevailing
hypotheses have been suggested to explain how this mutation leads to progressive loss of neurons. The gain of function
(GOF) hypothesis proposes that toxic molecules produced from the repeat expansion disrupt neural function and lead to
their destruction. The loss of function (LOF) hypothesis proposes that the C9ORF72 protein plays an important role in
support of neural function and survival and that reduced expression of this gene directly or indirectly sensitizes neurons to
disease. New evidence indicates that the mouse ortholog of C9ORF72 functions in the immune system to limit
inflammation and autoimmunity, although the exact mechanisms require further study. The first AIM of this proposal will
be to identify pathways and cell types that contribute to inflammation when the C9ORF72 ortholog is reduced and to
determine whether induced pluripotent stem cell-derived microglia-like cells from humans with the C9ORF72 repeat
expansion display similar inflammatory phenotypes. The second AIM of this proposal seeks to test the validity of the
LOF hypothesis in live organisms by injecting virus containing the hexanucleotide repeat expansion into mice that express
normal or reduced levels of the C9ORF72 ortholog. If lower levels of the C9ORF72 ortholog sensitize animals to toxic
features of the repeat expansion, this would provide support for developing therapies aimed at boosting levels of
C9ORF72 or inhibiting pathways affected by its reduction. The candidate will train with experts in diverse fields to
develop the technical skills necessary to complete these AIMs and to identify disease relevant pathways which can be
pursued in the independent phase of this proposal. Continued training with the candidate’s advisor and expert
collaborators will prepare him to succeed in his goal to run an independent research group in which he mentors
investigators of all levels and pursues hypotheses aimed at understanding etiologies of neurodegenerative disease.
项目摘要/摘要
与年龄相关的神经退行性疾病是社会的主要经济和情感负担,但到目前为止还没有
已经制定了预防策略。额颞性痴呆(FTD)和肌萎缩侧索硬化症(ALS)是
无情的进行性疾病,涉及对行为和肌肉运动至关重要的神经元退化,
分别进行了分析。C9ORF72基因非蛋白质编码区的六核苷酸重复扩增是最近被发现的
被发现是FTD和ALS最常见的原因,占所有诊断的10%。盛行的两个
已经提出了一些假设来解释这种突变是如何导致神经元的进行性丧失的。函数的增益
(GOF)假说提出,重复扩张产生的有毒分子扰乱神经功能,导致
他们的毁灭。功能丧失(LOF)假说认为C9ORF72蛋白在
支持神经功能和存活以及该基因表达减少直接或间接地使神经元对
疾病。新证据表明,C9ORF72小鼠同源基因在免疫系统中的作用有限
炎症和自身免疫,尽管确切的机制需要进一步研究。这项提案的第一个目标是
确定当C9ORF72同源基因减少时导致炎症的途径和细胞类型,并
检测C9ORF72重复序列是否能诱导人类多能干细胞来源的小胶质细胞样细胞
扩张表现出相似的炎症表型。这项建议的第二个目的是测试
通过将含有六核苷酸重复序列扩张的病毒注射到表达基因的小鼠体内,在活体中进行LOF假说
C9ORF72直系同源基因水平正常或降低。如果较低水平的C9ORF72同源基因使动物对有毒物质敏感
重复扩大的特点,这将为开发旨在提高水平的治疗提供支持
C9ORF72或受其还原影响的抑制通路。候选人将与不同领域的专家一起接受培训,以
培养完成这些目标所需的技术技能,并确定与疾病相关的途径
在本提案的独立阶段继续进行。与候选人的顾问和专家一起继续培训
合作者将为他成功实现他的目标做好准备,他将在其中指导一个独立的研究小组
所有级别的研究人员都在追寻假说,旨在了解神经退行性疾病的病因。
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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Aaron Burberry其他文献
Aaron Burberry的其他文献
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{{ truncateString('Aaron Burberry', 18)}}的其他基金
Exploring Mechanisms of Pathogenicity in C9ORF72 Frontotemporal Dementia and Amyotrophic Lateral Sclerosis
探索C9ORF72额颞叶痴呆和肌萎缩侧索硬化症的致病机制
- 批准号:
10382565 - 财政年份:2021
- 资助金额:
$ 10.85万 - 项目类别:
Exploring Mechanisms of Pathogenicity in C9ORF72 Frontotemporal Dementia and Amyotrophic Lateral Sclerosis
探索C9ORF72额颞叶痴呆和肌萎缩侧索硬化症的致病机制
- 批准号:
10599227 - 财政年份:2021
- 资助金额:
$ 10.85万 - 项目类别:
Exploring Mechanisms of Pathogenicity in C9ORF72 Frontotemporal Dementia and Amyotrophic Lateral Sclerosis
探索C9ORF72额颞叶痴呆和肌萎缩侧索硬化症的致病机制
- 批准号:
10437029 - 财政年份:2021
- 资助金额:
$ 10.85万 - 项目类别:
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