Identifying differences in dynamics and residual structure of intrinsically disordered domains between monomer and fibers: using alpha-synuclein as a model
识别单体和纤维之间本质无序域的动力学和残余结构的差异:使用α-突触核蛋白作为模型
基本信息
- 批准号:10607325
- 负责人:
- 金额:$ 4.77万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-01-19 至 2026-12-31
- 项目状态:未结题
- 来源:
- 关键词:AdoptedAffectAlzheimer&aposs DiseaseAmino Acid SequenceAmyloid FibrilsAmyloid beta-ProteinAntibodiesBindingBrainC-terminalCell CommunicationCell Culture TechniquesComplexDataDepositionDiseaseElectron Spin Resonance SpectroscopyFiberFutureGenetic PolymorphismHuntington geneIn VitroLengthLewy BodiesLigandsMediatingMethodsModelingMolecularMolecular ConformationMorphologyMotionMutagenesisNatureNeurodegenerative DisordersNeuronsParkinson DiseasePatientsPersonsPharmaceutical PreparationsPlayPolymorphPropertyProteinsResearchResidual stateResolutionRoleSeverity of illnessStructureSurfaceTestingTherapeuticToxic effectToxicity Testsalpha synucleinbeta pleated sheetbiophysical techniquesfiber cellflexibilityinsightmisfolded proteinmolecular dynamicsmonomerneuropathologypatient variabilitypreferenceprotein aggregationsolid state nuclear magnetic resonancesynucleinopathytau Proteins
项目摘要
PROJECT SUMMARY/ ABSTRACT
Many incurable neurodegenerative diseases including Alzheimer's, Parkinson's, and Huntingtin's feature the
presence of toxic misfolded proteins. These insoluble protein aggregates, amyloid fibrils (AF), have been
extensively studied and structural characterization has shown that they are largely composed of β-sheets and an
ordered cross-β fibril core; however, they are often framed by intrinsically disordered domains (IDDs) in the N
and C-terminal. Adding to the complex nature of AFs is the finding that many of them, including α-synuclein
(α-syn), amyloid-β, and tau, are found as polymorphs. Polymorphism, in this context, enables a protein to fold
and self-propagate into different AF structures often accompanied by varying neuropathology. The high
flexibility of the IDDs has made it difficult to take their molecular picture thus limiting our understanding of how
they affect AF properties in disease. Recent studies have demonstrated the importance of studying the IDDs of
AF as they have been found to play an important role in mediating fibril toxicity, aggregation, and interactions
with cellular components. α-Syn is natively found as a soluble intrinsically disordered protein (IDP), but in
Parkinson's disease it misfolds and aggregates into AF found in Lewy bodies. The importance of α-syn in disease
context has resulted in numerous studies of its monomeric and fibrillar form, thus the fibril core of α-syn is well-
characterized and there are several high-resolution structures available including at least four polymorph
structures. This makes α-syn an ideal candidate to determine the differences in structure and dynamics of the
IDDs in the monomeric and fibrillar state and between polymorphs. To accomplish this, I will use solid-state
nuclear magnetic resonance and electron paramagnetic resonance spectroscopy in combination with molecular
dynamics simulations to develop two full-length α-syn models that will describe the dynamic and structural
properties of IDDs in fibrils and it will provide insight on the effects of polymorphism on the IDDs. In addition,
polymorphs will be tested for toxicity in a neural cell culture model. This research will provide fundamental
understanding of AF that can help future studies that focus on understanding how IDDs mediate toxicity, fiber-
cell interactions, and seeding properties.
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 }}
Sayuri Pacheco其他文献
Sayuri Pacheco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
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:
$ 4.77万 - 项目类别:
Training 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:
$ 4.77万 - 项目类别:
Standard Grant
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:
$ 4.77万 - 项目类别:
Standard 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:
$ 4.77万 - 项目类别:
Fellowship
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:
$ 4.77万 - 项目类别:
Grant-in-Aid for Scientific Research (B)
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:
$ 4.77万 - 项目类别:
Research Grant
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:
$ 4.77万 - 项目类别:
Studentship
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:
$ 4.77万 - 项目类别:
Operating Grants
New Tendencies of French Film Theory: Representation, Body, Affect
法国电影理论新动向:再现、身体、情感
- 批准号:
23K00129 - 财政年份:2023
- 资助金额:
$ 4.77万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
The Protruding Void: Mystical Affect in Samuel Beckett's Prose
突出的虚空:塞缪尔·贝克特散文中的神秘影响
- 批准号:
2883985 - 财政年份:2023
- 资助金额:
$ 4.77万 - 项目类别:
Studentship