Structure and conformational diversity of amyloid oligomers
淀粉样蛋白寡聚物的结构和构象多样性
基本信息
- 批准号:7897965
- 负责人:
- 金额:$ 27.92万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2010
- 资助国家:美国
- 起止时间:2010-04-01 至 2015-03-31
- 项目状态:已结题
- 来源:
- 关键词:AddressAffinityAlzheimer&aposs DiseaseAmino Acid SequenceAmyloidAmyloid FibrilsAmyloid ProteinsAntibodiesAntibody SpecificityAssesBindingBrainBrain DiseasesCellsClassificationCognitiveConflict (Psychology)DataDepositionDevelopmentDiseaseEpitopesFaceGeneric DrugsGoalsHeterogeneityHigher Order Chromatin StructureHumanHuntington DiseaseImmune SeraImpaired cognitionIn VitroLaboratoriesLeadLigandsMolecular ConformationMonitorMonoclonal AntibodiesMutationNeurodegenerative DisordersNeuronsParkinson DiseasePathogenesisPathologyPathway interactionsPeptidesPharmaceutical PreparationsPlayPreparationPresenile Alzheimer DementiaPrincipal InvestigatorPrion DiseasesProtein PrecursorsProteinsPublishingRattusReagentReportingResearch Project GrantsRoleRunningSamplingSeedsSideSpecificityStructureTestingToxic effectTransgenic MiceVariantVertebral columnaggregation pathwayamyloid structurebasecellular targetingconformerinsightmonomerpreventprogramspublic health relevancesmall moleculesynthetic peptidetherapeutic developmenttherapeutic targetthree dimensional structure
项目摘要
DESCRIPTION (provided by applicant): The goal of this research project is to explore the structural heterogeneity of amyloid aggregates and the relationships of this conformational variation to the toxicity or pathogenic activities of amyloid oligomers. Several distinct types of amyloid deposits accumulate in disease brain and current evidence suggests that soluble, oligomeric forms of Ass may play primary role in pathogenesis. Recent results indicate that conformation-dependent monoclonal antibodies can distinguish between different types soluble Ass oligomers. These antibodies also distinguish other conformations of Ass, including monomers, fibrils and natively-folded APP. We have recently prepared two additional conformation-dependent antisera that recognize generic epitopes associated with amyloid fibrils and pore-like annular protofibrils that are formed from many different types of amyloids (see Preliminary Data, below). These antibodies are complementary to the anti-oligomer antibody, A11 and recognize epitopes that are specific to fibrils and annular protofibril aggregates. We hypothesize that these conformationally distinct assembly states of Ass are differentially associated with AD pathogenesis. We anticipate that these results will help clarify some apparent inconsistencies and conflicting data, such as the observations that the total Ass amyloid deposited correlates poorly with disease and some people have large amounts of amyloid and are cognitive normal, while other brain samples that have little observable amyloid deposits are associated with cognitive dysfunction. We hypothesize that the distinct types of soluble oligomeric or annular protofibril forms of Ass have distinct toxicities. Conformation-dependent antibodies hold the potential of identifying and distinguishing specific assembly states because they only recognize a specific misfolded state and do not react with the natively folded precursor protein. The specific aims of this project will address the following questions: What is the conformational diversity of amyloid aggregates? What is the structural basis of conformation dependent antibody specificity and amyloid oligomer structural? What are the relationships between different conformational states of amyloids? What is the pathological significance of the different amyloid conformational states? The answers to these questions should provide insight into the range of amyloid oligomer conformational diversity and monoclonal antibody reagents that distinguish different conformations of oligomers. This may provide a more rational structural basis for the classification of oligomers and provide insight into the variability in oligomer preparations reported by different laboratories. Determining the 3 dimensional structure of the monoclonal Fabs bound to amyloid oligomers may provide unprecedented insight into the structure of amyloid oligomers and the mechanism of specific antibody recognition that may be useful for development of immunological therapeutics that target oligomer formation or prevent their interaction with cellular targets. The identification of small molecules that specifically inhibit the formation of different types of oligomers should help to clarify whether the oligomers are intermediates in the formation of higher order structures, like fibrils or whether they represent stable alternative end products. This aim may also provide small molecule lead compounds that specifically inhibit amyloid oligomer formation for therapeutic development. The characterization of which types of amyloid oligomers are more closely related to pathogenesis in human and transgenic mouse brain may help to identify targets for therapeutic development. PHS 398/2590 (Rev. 04/06) Page Continuation Format Page
PUBLIC HEALTH RELEVANCE: Amyloid aggregates are believed to play a central role in the development of neurodegenerative diseases, like Alzheimer, Parkinson, Huntington and prion diseases. The goal of this proposal is to determine how many different types of amyloid aggregates exist and to determine the precise 3 dimensional structure of the amyloid aggregates. The proposal will also examine which of these aggregates is more toxic to neurons and most closely related to disease. An additional benefit is that this proposal may produce monoclonal antibodies and drugs that specifically target these amyloid aggregates for therapeutic development.
描述(由申请人提供):本研究项目的目标是探索淀粉样蛋白聚集体的结构异质性以及这种构象变化与淀粉样蛋白低聚物的毒性或致病活性的关系。几种不同类型的淀粉样蛋白沉积在疾病大脑中积累,目前的证据表明可溶性低聚形式的淀粉样蛋白可能在发病机制中起主要作用。最近的研究表明,构象依赖的单克隆抗体可以区分不同类型的可溶性Ass低聚物。这些抗体还可以区分Ass的其他构象,包括单体、原纤维和天然折叠的APP。我们最近制备了另外两种构象依赖的抗血清,它们可以识别与淀粉样原纤维和孔样环状原纤维相关的通用表位,这些原纤维是由许多不同类型的淀粉样蛋白形成的(见下面的初步数据)。这些抗体与抗低聚物抗体A11互补,并识别原纤维和环状原纤维聚集物特异性的表位。我们假设这些构象上不同的Ass组装状态与AD的发病机制有不同的关联。我们预计这些结果将有助于澄清一些明显的不一致和相互矛盾的数据,例如观察到总的淀粉样蛋白沉积与疾病的相关性很差,一些人有大量的淀粉样蛋白并且认知正常,而其他大脑样本中几乎没有可观察到的淀粉样蛋白沉积与认知功能障碍有关。我们假设不同类型的可溶性低聚物或环状原纤维形式的Ass具有不同的毒性。构象依赖性抗体具有识别和区分特定组装状态的潜力,因为它们只识别特定的错误折叠状态,而不与天然折叠的前体蛋白发生反应。该项目的具体目标将解决以下问题:淀粉样蛋白聚集体的构象多样性是什么?构象依赖性抗体特异性和淀粉样低聚物结构的结构基础是什么?淀粉样蛋白的不同构象状态之间有什么关系?淀粉样蛋白不同构象状态的病理意义是什么?这些问题的答案应该提供洞察淀粉样蛋白低聚物构象多样性和单克隆抗体试剂区分不同的低聚物构象的范围。这可能为低聚物的分类提供更合理的结构基础,并为不同实验室报道的低聚物制剂的可变性提供见解。确定与淀粉样蛋白低聚物结合的单克隆fab的三维结构可能为淀粉样蛋白低聚物的结构和特异性抗体识别机制提供前所未有的见解,这可能有助于开发针对低聚物形成或阻止其与细胞靶标相互作用的免疫疗法。鉴定特异性抑制不同类型低聚物形成的小分子应该有助于澄清低聚物是形成高阶结构(如原纤维)的中间产物,还是代表稳定的替代最终产物。这一目标也可能为治疗开发提供特异性抑制淀粉样蛋白低聚物形成的小分子先导化合物。确定哪些类型的淀粉样蛋白低聚物与人类和转基因小鼠大脑的发病机制更密切相关,可能有助于确定治疗开发的靶点。小灵通398/2590 (Rev. 04/06)页延续格式页
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 }}
Charles G. Glabe其他文献
Amyloid Oligomers Increase the Lifetime and Single Channel Conductance of Gramicidin Channels
- DOI:
10.1016/j.bpj.2009.12.1527 - 发表时间:
2010-01-01 - 期刊:
- 影响因子:
- 作者:
Yuri Sokolov;Saskia C. Milton;Charles G. Glabe;James E. Hall - 通讯作者:
James E. Hall
Amyloid Oligomers Increase the Lifetime and Single Channel Conductance of Gramicidin Channels
- DOI:
10.1016/j.bpj.2010.12.2034 - 发表时间:
2011-02-02 - 期刊:
- 影响因子:
- 作者:
Yuri V. Sokolov;Saskia C. Milton;Charles G. Glabe;James E. Hall - 通讯作者:
James E. Hall
Die spezifische Zellerkennung
特殊的泽勒肯农
- DOI:
10.1002/ciuz.19940280111 - 发表时间:
1994 - 期刊:
- 影响因子:0.8
- 作者:
A. Hofmann;Charles G. Glabe - 通讯作者:
Charles G. Glabe
RETRACTED ARTICLE: A specific amyloid-β protein assembly in the brain impairs memory
撤回文章:大脑中一种特定的淀粉样β蛋白聚集体损害记忆
- DOI:
10.1038/nature04533 - 发表时间:
2006-03-16 - 期刊:
- 影响因子:48.500
- 作者:
Sylvain Lesné;Ming Teng Koh;Linda Kotilinek;Rakez Kayed;Charles G. Glabe;Austin Yang;Michela Gallagher;Karen H. Ashe - 通讯作者:
Karen H. Ashe
Amyloid Oligomers Alter The Conductance Of The Gramicidin Channel
- DOI:
10.1016/j.bpj.2008.12.719 - 发表时间:
2009-02-01 - 期刊:
- 影响因子:
- 作者:
Yuri V. Sokolov;Saskia C. Milton;Charles G. Glabe;James E. Hall - 通讯作者:
James E. Hall
Charles G. Glabe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('Charles G. Glabe', 18)}}的其他基金
Shared resource to develop tools and reagents to study structural polymorphisms in Abeta amyloid aggregates in AD
共享资源开发工具和试剂来研究 AD 中 Abeta 淀粉样蛋白聚集体的结构多态性
- 批准号:
10706566 - 财政年份:2022
- 资助金额:
$ 27.92万 - 项目类别:
Shared resource to develop tools and reagents to study structural polymorphisms in Abeta amyloid aggregates in AD
共享资源开发工具和试剂来研究 AD 中 Abeta 淀粉样蛋白聚集体的结构多态性
- 批准号:
10549101 - 财政年份:2022
- 资助金额:
$ 27.92万 - 项目类别:
Temporal, Spatial and Cellular Dynamics of Amyloid Plaque Deposition
淀粉样蛋白斑沉积的时间、空间和细胞动力学
- 批准号:
10525630 - 财政年份:2022
- 资助金额:
$ 27.92万 - 项目类别:
Structure and conformational diversity of amyloid oligomers
淀粉样蛋白寡聚物的结构和构象多样性
- 批准号:
8235899 - 财政年份:2010
- 资助金额:
$ 27.92万 - 项目类别:
Structure and conformational diversity of amyloid oligomers
淀粉样蛋白寡聚物的结构和构象多样性
- 批准号:
8445260 - 财政年份:2010
- 资助金额:
$ 27.92万 - 项目类别:
Structure and conformational diversity of amyloid oligomers
淀粉样蛋白寡聚物的结构和构象多样性
- 批准号:
8053831 - 财政年份:2010
- 资助金额:
$ 27.92万 - 项目类别:
STRUCTURE & CONFORMATIONAL DIVERSITY OF AMYLOID AGGREGATES BY FCS
结构
- 批准号:
8170964 - 财政年份:2010
- 资助金额:
$ 27.92万 - 项目类别:
SITE-SPECIFIC STUDIES PROVIDE STRUCTURAL INFORMATION ON AMYLOID BETA OLIGOMERS
特定位点研究提供了淀粉样β低聚物的结构信息
- 批准号:
8170990 - 财政年份:2010
- 资助金额:
$ 27.92万 - 项目类别:
STRUCTURE & CONFORMATIONAL DIVERSITY OF AMYLOID AGGREGATES BY FCS
结构
- 批准号:
7956535 - 财政年份:2009
- 资助金额:
$ 27.92万 - 项目类别:
Amyloid Accumulation Mechanisms/Pathogenesis in AD Brain
AD 脑中淀粉样蛋白积累机制/发病机制
- 批准号:
6587293 - 财政年份:2002
- 资助金额:
$ 27.92万 - 项目类别:
相似海外基金
Construction of affinity sensors using high-speed oscillation of nanomaterials
利用纳米材料高速振荡构建亲和传感器
- 批准号:
23H01982 - 财政年份:2023
- 资助金额:
$ 27.92万 - 项目类别:
Grant-in-Aid for Scientific Research (B)
Affinity evaluation for development of polymer nanocomposites with high thermal conductivity and interfacial molecular design
高导热率聚合物纳米复合材料开发和界面分子设计的亲和力评估
- 批准号:
23KJ0116 - 财政年份:2023
- 资助金额:
$ 27.92万 - 项目类别:
Grant-in-Aid for JSPS Fellows
Development of High-Affinity and Selective Ligands as a Pharmacological Tool for the Dopamine D4 Receptor (D4R) Subtype Variants
开发高亲和力和选择性配体作为多巴胺 D4 受体 (D4R) 亚型变体的药理学工具
- 批准号:
10682794 - 财政年份:2023
- 资助金额:
$ 27.92万 - 项目类别:
Platform for the High Throughput Generation and Validation of Affinity Reagents
用于高通量生成和亲和试剂验证的平台
- 批准号:
10598276 - 财政年份:2023
- 资助金额:
$ 27.92万 - 项目类别:
Collaborative Research: DESIGN: Co-creation of affinity groups to facilitate diverse & inclusive ornithological societies
合作研究:设计:共同创建亲和团体以促进多元化
- 批准号:
2233343 - 财政年份:2023
- 资助金额:
$ 27.92万 - 项目类别:
Standard Grant
Collaborative Research: DESIGN: Co-creation of affinity groups to facilitate diverse & inclusive ornithological societies
合作研究:设计:共同创建亲和团体以促进多元化
- 批准号:
2233342 - 财政年份:2023
- 资助金额:
$ 27.92万 - 项目类别:
Standard Grant
Molecular mechanisms underlying high-affinity and isotype switched antibody responses
高亲和力和同种型转换抗体反应的分子机制
- 批准号:
479363 - 财政年份:2023
- 资助金额:
$ 27.92万 - 项目类别:
Operating Grants
Deconstructed T cell antigen recognition: Separation of affinity from bond lifetime
解构 T 细胞抗原识别:亲和力与键寿命的分离
- 批准号:
10681989 - 财政年份:2023
- 资助金额:
$ 27.92万 - 项目类别:
CAREER: Engineered Affinity-Based Biomaterials for Harnessing the Stem Cell Secretome
职业:基于亲和力的工程生物材料用于利用干细胞分泌组
- 批准号:
2237240 - 财政年份:2023
- 资助金额:
$ 27.92万 - 项目类别:
Continuing Grant
ADVANCE Partnership: Leveraging Intersectionality and Engineering Affinity groups in Industrial Engineering and Operations Research (LINEAGE)
ADVANCE 合作伙伴关系:利用工业工程和运筹学 (LINEAGE) 领域的交叉性和工程亲和力团体
- 批准号:
2305592 - 财政年份:2023
- 资助金额:
$ 27.92万 - 项目类别:
Continuing Grant