The impact of post-translational modification on SOD1 aggregation in ALS
翻译后修饰对 ALS 中 SOD1 聚集的影响
基本信息
- 批准号:8219212
- 负责人:
- 金额:$ 3.05万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2011
- 资助国家:美国
- 起止时间:2011-02-01 至 2014-01-31
- 项目状态:已结题
- 来源:
- 关键词:AddressAffectAmyotrophic Lateral SclerosisAntioxidantsAppearanceBehaviorCessation of lifeChargeCuprozinc Superoxide DismutaseDepositionDiseaseDisease OutcomeDissociationEnvironmentEnzymesEquilibriumErythrocytesEtiologyEvaluationFamilial Amyotrophic Lateral SclerosisGoalsHoloenzymesHumanIn VitroInheritedInvestigationKnowledgeLeadLifeLightLinkMeasurableMeasuresModificationMolecular Sieve ChromatographyMonitorMotor NeuronsMutationNeurodegenerative DisordersPathogenesisPathway interactionsPatientsPhosphorylationPhysiologicalPost-Translational Protein ProcessingPrevention approachProcessProductionPropertyProteinsReportingResearchRoleSourceStructureSurface Plasmon ResonanceSymptomsTechniquesTestingTherapeutic InterventionThreonineTimeToxic effectTranslationsUnited StatesWorkaggregation pathwaycytotoxicdimereffective therapygain of functionin vivoinsightmonomermutantneurotoxicitynovelnovel therapeutic interventionpublic health relevance
项目摘要
DESCRIPTION (provided by applicant): Amyotrophic lateral sclerosis (ALS) is a progressive, late-onset neurodegenerative disorder for which there is currently no effective treatment, and which affects nearly 30,000 people in the United States. A subset of ALS cases are caused by mutations in the ubiquitous antioxidant enzyme Cu, Zn superoxide dismutase (SOD1) through an ill-defined toxic gain of function. The accumulation of misfolded and/or aggregated SOD1 in dying motor neurons suggests that SOD1-related ALS is primarily a protein deposition disorder. However, little is known about the causes, mechanism, and consequences of SOD1 oligomerization in ALS. The long term objective of the proposed work is the elucidation of the mechanism(s) by which SOD1 forms non-native oligomers. As ALS symptoms typically do not appear until late in life, we hypothesize that factors in the cellular environment likely influence oligomer formation and subsequent motor neuron toxicity. In the aims proposed here, we will examine the effect of two physiological post-translational modifications, phosphorylation and glutathionylation, on the structural transitions of SOD1 from native to aggregated states. The first specific aim will focus on the first step in oligomer formation, dissociation of the native SOD1 homodimer. Crystal structures of modified SOD1 will be solved and assessed for any perturbations in the dimeric structure. Aim 2 will test the effect of modification on the oligomerization dynamics of wild type and mutant SOD1. Biophysical techniques such as surface plasmon resonance and size exclusion chromatography will be used to monitor the rate of dimer dissociation and appearance of non-native oligomeric species. By studying modified and unmodified forms of wild-type SOD1 as well as a diverse set of ALS-associated mutants, we will determine whether modifications and mutations produce a cumulative increase in SOD1 aggregation propensity. The studies proposed here would enhance the currently meager understanding of the general SOD1 oligomerization pathway and provide novel insight on how this process is affected by physiological post-translation modifications. As aggregation is a central pathological feature of SOD1-related ALS, knowledge of this process and its cellular determinants would lead to more effective treatments and preventative measures.
PUBLIC HEALTH RELEVANCE: Amyotrophic lateral sclerosis (ALS) is an aggressive neurodegenerative disorder in which misfolded and aggregated forms of Cu, Zn- superoxide dismutase (SOD1) cause selective death of motor neurons. This project will examine how post-translational modifications and mutations of SOD1, individually and in tandem, affect the tendency of the protein to aggregate. Understanding of the factors that influence SOD1 aggregation can be used to develop novel therapeutic approaches to the prevention or mitigation of ALS symptoms.
描述(由申请人提供):肌萎缩侧索硬化症(ALS)是一种进行性、迟发性神经退行性疾病,目前尚无有效治疗方法,在美国影响近30,000人。ALS病例的一个子集是由普遍存在的抗氧化酶Cu,Zn超氧化物歧化酶(SOD 1)的突变通过功能的不明确的毒性获得引起的。死亡的运动神经元中错误折叠和/或聚集的SOD 1的积累表明,SOD 1相关的ALS主要是一种蛋白质沉积障碍。然而,关于ALS中SOD 1寡聚化的原因、机制和后果知之甚少。拟议工作的长期目标是阐明SOD 1形成非天然寡聚体的机制。由于ALS症状通常直到生命后期才出现,我们假设细胞环境中的因素可能影响寡聚体形成和随后的运动神经元毒性。在这里提出的目标,我们将研究两个生理的翻译后修饰,磷酸化和谷胱甘肽化,对SOD 1从天然到聚集状态的结构转变的影响。第一个具体目标将集中在低聚物形成的第一步,即天然SOD 1同二聚体的解离。将求解修饰的SOD 1的晶体结构并评估二聚体结构中的任何扰动。目的2将测试修饰对野生型和突变体SOD 1的寡聚动力学的影响。生物物理技术,如表面等离子体共振和尺寸排阻色谱法将用于监测二聚体解离速率和非天然寡聚体物质的出现。通过研究野生型SOD 1的修饰和未修饰形式以及各种ALS相关突变体,我们将确定修饰和突变是否会导致SOD 1聚集倾向的累积增加。本文提出的研究将增强目前对一般SOD 1寡聚化途径的贫乏理解,并提供关于该过程如何受生理翻译后修饰影响的新见解。由于聚集是SOD 1相关ALS的核心病理特征,因此了解这一过程及其细胞决定因素将有助于更有效的治疗和预防措施。
公共卫生关系:肌萎缩侧索硬化症(ALS)是一种侵袭性神经退行性疾病,其中Cu,Zn-超氧化物歧化酶(SOD 1)的错误折叠和聚集形式导致运动神经元的选择性死亡。该项目将研究SOD 1的翻译后修饰和突变如何单独和串联影响蛋白质聚集的趋势。了解影响SOD 1聚集的因素可用于开发预防或缓解ALS症状的新治疗方法。
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 }}
Rachel Redler其他文献
Rachel Redler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('Rachel Redler', 18)}}的其他基金
The impact of post-translational modification on SOD1 aggregation in ALS
翻译后修饰对 ALS 中 SOD1 聚集的影响
- 批准号:
8416974 - 财政年份:2011
- 资助金额:
$ 3.05万 - 项目类别:
The impact of post-translational modification on SOD1 aggregation in ALS
翻译后修饰对 ALS 中 SOD1 聚集的影响
- 批准号:
8060912 - 财政年份:2011
- 资助金额:
$ 3.05万 - 项目类别:
相似海外基金
RII Track-4:NSF: From the Ground Up to the Air Above Coastal Dunes: How Groundwater and Evaporation Affect the Mechanism of Wind Erosion
RII Track-4:NSF:从地面到沿海沙丘上方的空气:地下水和蒸发如何影响风蚀机制
- 批准号:
2327346 - 财政年份:2024
- 资助金额:
$ 3.05万 - 项目类别:
Standard Grant
BRC-BIO: Establishing Astrangia poculata as a study system to understand how multi-partner symbiotic interactions affect pathogen response in cnidarians
BRC-BIO:建立 Astrangia poculata 作为研究系统,以了解多伙伴共生相互作用如何影响刺胞动物的病原体反应
- 批准号:
2312555 - 财政年份:2024
- 资助金额:
$ 3.05万 - 项目类别:
Standard Grant
How Does Particle Material Properties Insoluble and Partially Soluble Affect Sensory Perception Of Fat based Products
不溶性和部分可溶的颗粒材料特性如何影响脂肪基产品的感官知觉
- 批准号:
BB/Z514391/1 - 财政年份:2024
- 资助金额:
$ 3.05万 - 项目类别:
Training Grant
Graduating in Austerity: Do Welfare Cuts Affect the Career Path of University Students?
紧缩毕业:福利削减会影响大学生的职业道路吗?
- 批准号:
ES/Z502595/1 - 财政年份:2024
- 资助金额:
$ 3.05万 - 项目类别:
Fellowship
Insecure lives and the policy disconnect: How multiple insecurities affect Levelling Up and what joined-up policy can do to help
不安全的生活和政策脱节:多种不安全因素如何影响升级以及联合政策可以提供哪些帮助
- 批准号:
ES/Z000149/1 - 财政年份:2024
- 资助金额:
$ 3.05万 - 项目类别:
Research Grant
感性個人差指標 Affect-X の構築とビスポークAIサービスの基盤確立
建立个人敏感度指数 Affect-X 并为定制人工智能服务奠定基础
- 批准号:
23K24936 - 财政年份:2024
- 资助金额:
$ 3.05万 - 项目类别:
Grant-in-Aid for Scientific Research (B)
How does metal binding affect the function of proteins targeted by a devastating pathogen of cereal crops?
金属结合如何影响谷类作物毁灭性病原体靶向的蛋白质的功能?
- 批准号:
2901648 - 财政年份:2024
- 资助金额:
$ 3.05万 - 项目类别:
Studentship
ERI: Developing a Trust-supporting Design Framework with Affect for Human-AI Collaboration
ERI:开发一个支持信任的设计框架,影响人类与人工智能的协作
- 批准号:
2301846 - 财政年份:2023
- 资助金额:
$ 3.05万 - 项目类别:
Standard Grant
Investigating how double-negative T cells affect anti-leukemic and GvHD-inducing activities of conventional T cells
研究双阴性 T 细胞如何影响传统 T 细胞的抗白血病和 GvHD 诱导活性
- 批准号:
488039 - 财政年份:2023
- 资助金额:
$ 3.05万 - 项目类别:
Operating Grants
How motor impairments due to neurodegenerative diseases affect masticatory movements
神经退行性疾病引起的运动障碍如何影响咀嚼运动
- 批准号:
23K16076 - 财政年份:2023
- 资助金额:
$ 3.05万 - 项目类别:
Grant-in-Aid for Early-Career Scientists