Guanabenz in the treatment of mutant SOD1 ALS mice
胍那苯治疗突变型 SOD1 ALS 小鼠
基本信息
- 批准号:8280775
- 负责人:
- 金额:$ 23.4万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2012
- 资助国家:美国
- 起止时间:2012-03-15 至 2014-02-28
- 项目状态:已结题
- 来源:
- 关键词:AP20187Amyotrophic Lateral SclerosisAntihypertensive AgentsApoptosisBindingBlood - brain barrier anatomyCCAAT-Enhancer-Binding ProteinsCatalytic DomainCellsCuprozinc Superoxide DismutaseCytoplasmic GranulesDNA DamageDataDimerizationDiseaseDrug KineticsFDA approvedFamilial Amyotrophic Lateral SclerosisGenesGenetic TranscriptionGrowthGuanabenzHomeostasisHomologous ProteinInheritance PatternsInositolLeadMolecular ChaperonesMotor NeuronsMusMutateMutationNeurodegenerative DisordersOxidation-ReductionPancreasPathway interactionsPharmaceutical PreparationsPhosphorylationPhosphotransferasesPrionsProtein DephosphorylationProtein phosphataseProteinsPublishingRepressionResearch PersonnelSafetyScrapieSignal TransductionStressTestingToxic effectTransgenic MiceTranslatingTranslational RepressionTranslationsactivating transcription factorbiological adaptation to stresseffective therapyefficacy testinggain of functionkillingsloss of functionmutantprotein TDP-43protein degradationprotein misfoldingresponsesensortissue/cell culturetranscription factortranscription factor ATF6vector
项目摘要
DESCRIPTION (provided by applicant): Our planned studies may provide new targets and treatment directions in amyotrophic lateral sclerosis (ALS), a fatal disease with no cure. Mutant (mt) SOD1 is thought to cause familial ALS (FALS) because of a gain in function probably involving misfolding of the protein. We recently published data that show that haploinsufficiency of PERK (which as part of the unfolded protein response [UPR] leads to phosphorylation of eIF2¿ with a subsequent suppression of translation) accelerates disease in G85R mtSOD1 FALS transgenic mice and have preliminary unpublished data that show that a knockdown of GADD34 (which dephosphorylates eIF2¿) ameliorates disease. These data have led to the hypothesis underlying this proposal: an enhancement of PERK and the PERK pathway will ameliorate disease. In Specific Aim I, we will test the efficacy of an FDA-approved drug, guanabenz, in ameliorating disease in G85R mtSOD1 FALS mice. Guanabenz was previously shown to promote clearance of scrapie prion protein (PrPsc) (a misfolded protein) in tissue-culture cells and also to significantly prolong survival of PrPsc transgenic mice. Guanabenz was very recently found to bind to a regulatory subunit of protein phosphatase 1, PPP1R15A/GADD34, selectively disrupting the stress-induced dephosphorylation of eIF2¿. Guanabenz is an especially attractive drug for the treatment of FALS because a great deal is known about its pharmacokinetics (e.g., it is known to cross the blood-brain barrier) and safety due to its present use as an antihypertensive. In Specific Aim II, we plan to activate PERK before the stress response is triggered, and also enhance PERK above the normal endogenous levels during ER stress (e.g., during disease). We will use adeno-associated virus9 (AAV9) to deliver Fv2E-PERK, which contains the kinase domain of PERK (that is normally activated by dimerization) fused to a protein module. Administration of a small dimerizer molecule (AP20187) leads to PERK activation, even in the absence of a stress response. The results of our studies will have implications for sporadic ALS as well as FALS because: recent data suggest that sporadic ALS may also involve abnormalities in the SOD1 protein or its activity; TDP-43, which is implicated in sporadic ALS and FALS, has potential interactions with the UPR since TDP-43 is misfolded in these diseases and because TDP-43 is a constituent of stress granules-which can form as a result of the UPR.
PUBLIC HEALTH RELEVANCE: Amyotrophic lateral sclerosis (ALS) is a desperate disease for which there is no cure and no effective treatment. It is accepted by many investigators that mutations in SOD1 cause familial ALS because they lead to misfolding of the protein. This proposal involves two different treatment approaches that allow the cell to enhance its normal response to misfolded proteins.
描述(申请人提供):我们计划的研究可能为肌萎缩侧索硬化症(ALS)提供新的靶点和治疗方向,ALS是一种无法治愈的致命疾病。突变(Mt)SOD1被认为是导致家族性肌萎缩侧索硬化症(FALS)的原因,因为功能增强可能涉及蛋白质的错误折叠。我们最近发表的数据表明,PERK(作为未折叠蛋白反应[UPR]的一部分,导致eIF2?的磷酸化,并随后抑制翻译)的单倍性不足会加速G85R mtSOD1FALS转基因小鼠的疾病,并且有初步的未发表的数据表明,Gadd34的敲除(去磷酸化eIF2?)可以改善疾病。这些数据导致了这一提议背后的假设:PERK和PERK途径的增强将改善疾病。在特定的目标I中,我们将测试FDA批准的药物guanabenz在改善G85R mtSOD1FALS小鼠疾病方面的有效性。先前的研究表明,愈那苯能促进组织培养细胞中PrPsc(一种错误折叠的蛋白质)的清除,还能显著延长PrPsc转基因小鼠的存活时间。Ganabenz最近被发现与蛋白磷酸酶1的一个调节亚基PPP1R15A/Gadd34结合,选择性地破坏应激诱导的eIF2的去磷酸化。Ganabenz是一种特别有吸引力的治疗FALS的药物,因为人们对它的药代动力学(例如,已知它可以穿越血脑屏障)和安全性已知很多,因为它目前用作抗高血压药物。在特定的目标II中,我们计划在应激反应被触发之前激活PERK,并在内质网应激期间(例如,在疾病期间)将PERK提高到高于正常内源性水平。我们将使用腺相关病毒9(AAV9)来传递Fv2E-PERK,它包含PERK的激活域(通常通过二聚化激活)与蛋白质模块融合。即使在没有应激反应的情况下,给予小二聚体分子(AP20187)也会导致PERK激活。我们的研究结果将对散发性ALS以及FAL产生影响,因为:最近的数据表明,散发性ALS也可能涉及SOD1蛋白或其活性的异常;TDP-43与散发性ALS和FAL有关,具有潜在的与UPR的相互作用,因为TDP-43在这些疾病中错误折叠,并且因为TDP-43是应激颗粒的组成部分-这可能是UPR的结果。
公共卫生相关性:肌萎缩侧索硬化症(ALS)是一种无法治愈、也没有有效治疗方法的绝症。许多研究人员认为SOD1基因突变会导致家族性肌萎缩侧索硬化症,因为它们会导致蛋白质的错误折叠。这项建议涉及两种不同的治疗方法,允许细胞增强其对错误折叠的蛋白质的正常反应。
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 }}
RAYMOND Philip ROOS其他文献
RAYMOND Philip ROOS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('RAYMOND Philip ROOS', 18)}}的其他基金
Pathogenesis of Theiler's virus-induced demyelinating disease
泰勒病毒引起的脱髓鞘病的发病机制
- 批准号:
9093302 - 财政年份:2016
- 资助金额:
$ 23.4万 - 项目类别:
Guanabenz in the treatment of mutant SOD1 ALS mice
胍那苯治疗突变型 SOD1 ALS 小鼠
- 批准号:
8442820 - 财政年份:2012
- 资助金额:
$ 23.4万 - 项目类别:
Single chain Fragments of variable regions in the treatment of Familial ALS
可变区单链片段治疗家族性肌萎缩侧索硬化症
- 批准号:
7904720 - 财政年份:2010
- 资助金额:
$ 23.4万 - 项目类别:
Single chain Fragments of variable regions in the treatment of Familial ALS
可变区单链片段治疗家族性肌萎缩侧索硬化症
- 批准号:
8049184 - 财政年份:2010
- 资助金额:
$ 23.4万 - 项目类别:
Preparing Trainees in Neurology and Neurosurgery for Academic Research Careers
为神经病学和神经外科学员的学术研究职业做好准备
- 批准号:
8238678 - 财政年份:2009
- 资助金额:
$ 23.4万 - 项目类别:
Preparing Trainees in Neurology and Neurosurgery for Academic Research Careers
为神经病学和神经外科学员的学术研究职业做好准备
- 批准号:
8036079 - 财政年份:2009
- 资助金额:
$ 23.4万 - 项目类别:
Preparing Trainees in Neurology and Neurosurgery for Academic Research Careers
为神经病学和神经外科学员的学术研究职业做好准备
- 批准号:
7779486 - 财政年份:2009
- 资助金额:
$ 23.4万 - 项目类别:
Preparing Trainees in Neurology and Neurosurgery for Academic Research Careers
为神经病学和神经外科学员的学术研究职业做好准备
- 批准号:
8435565 - 财政年份:2009
- 资助金额:
$ 23.4万 - 项目类别:
Preparing Trainees in Neurology and Neurosurgery for Academic Research Careers
为神经病学和神经外科学员的学术研究职业做好准备
- 批准号:
8233407 - 财政年份:2009
- 资助金额:
$ 23.4万 - 项目类别:
Preparing Trainees in Neurology and Neurosurgery for Academic Research Careers
为神经病学和神经外科学员的学术研究职业做好准备
- 批准号:
8574844 - 财政年份:2009
- 资助金额:
$ 23.4万 - 项目类别:
相似海外基金
Amyotrophic Lateral Sclerosis: treating the circuit behind the disease
肌萎缩侧索硬化症:治疗疾病背后的回路
- 批准号:
MR/Y014901/1 - 财政年份:2024
- 资助金额:
$ 23.4万 - 项目类别:
Research Grant
Dysregulation of RNA processing as a driver of motor neuron dysfunction in Amyotrophic Lateral Sclerosis
RNA 加工失调是肌萎缩侧索硬化症运动神经元功能障碍的驱动因素
- 批准号:
MR/Y014286/1 - 财政年份:2024
- 资助金额:
$ 23.4万 - 项目类别:
Research Grant
Fasciculation IN Amyotrophic Lateral Sclerosis Using MUMRI (FINALSUM)
使用 MUMRI 治疗肌萎缩侧索硬化症的肌束颤动 (FINALSUM)
- 批准号:
MR/Y503502/1 - 财政年份:2024
- 资助金额:
$ 23.4万 - 项目类别:
Research Grant
I-Corps: Developing A Blood-Based Biomarker for the Detection and Monitoring of Amyotrophic Lateral Sclerosis
I-Corps:开发一种基于血液的生物标志物,用于检测和监测肌萎缩侧索硬化症
- 批准号:
2317745 - 财政年份:2023
- 资助金额:
$ 23.4万 - 项目类别:
Standard Grant
Development of CM-CS1 CAR Treg to Treat Amyotrophic Lateral Sclerosis (ALS)
开发 CM-CS1 CAR Treg 治疗肌萎缩侧索硬化症 (ALS)
- 批准号:
10696512 - 财政年份:2023
- 资助金额:
$ 23.4万 - 项目类别:
Targeted immunotherapy for amyotrophic lateral sclerosis and frontotemporal dementia
肌萎缩侧索硬化症和额颞叶痴呆的靶向免疫治疗
- 批准号:
10759808 - 财政年份:2023
- 资助金额:
$ 23.4万 - 项目类别:
Metrics for Brain Controlled Communication: A comprehensive review of clinical outcome assessments for communication brain computer interfaces in amyotrophic lateral sclerosis
脑控制通信指标:肌萎缩侧索硬化症通信脑机接口临床结果评估的全面综述
- 批准号:
10848139 - 财政年份:2023
- 资助金额:
$ 23.4万 - 项目类别:
Resolving the Role of Neuronal STING in Amyotrophic Lateral Sclerosis and Frontotemporal Dementia
解决神经元 STING 在肌萎缩侧索硬化症和额颞叶痴呆中的作用
- 批准号:
10606865 - 财政年份:2023
- 资助金额:
$ 23.4万 - 项目类别:
The biochemical stratification of amyotrophic lateral sclerosis
肌萎缩侧索硬化症的生化分层
- 批准号:
MR/Y001095/1 - 财政年份:2023
- 资助金额:
$ 23.4万 - 项目类别:
Fellowship
The Gut Microbiota as a Contributor to Sexual Dimorphism in Amyotrophic Lateral Sclerosis
肠道微生物群是肌萎缩侧索硬化症性别二态性的一个促成因素
- 批准号:
488892 - 财政年份:2023
- 资助金额:
$ 23.4万 - 项目类别:
Operating Grants