Functional Analysis of O-GlcNAc using Synthetic Protein Chemistry
使用合成蛋白质化学对 O-GlcNAc 进行功能分析
基本信息
- 批准号:10460615
- 负责人:
- 金额:$ 34.69万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2015
- 资助国家:美国
- 起止时间:2015-08-01 至 2025-07-31
- 项目状态:未结题
- 来源:
- 关键词:AcetylationAffectAmyloidAnimalsBiochemicalBiochemistryBiologicalBiologyBiophysicsCarbohydratesCellular biologyCharcot-Marie-Tooth DiseaseChemicalsCollaborationsCryoelectron MicroscopyDataDevelopmentDiabetes MellitusDiffusionDiseaseEmbryonic DevelopmentExcisionFunctional disorderFundingGoalsGrantHSPB1 geneHeat shock proteinsKineticsKnowledgeLigationMalignant NeoplasmsMammalsMeasuresMethodsMichiganModificationMolecularMolecular ChaperonesMonosaccharidesMusMutagenesisMutationNerve DegenerationNeurodegenerative DisordersNeuronsNeuropathyO-GlcNAc transferaseParkinson DiseasePathogenicityPathway interactionsPatientsPeripheral Nervous System DiseasesPhosphorylationPlayPoint MutationPolymorphPost-Translational Protein ProcessingProtein ChemistryProteinsProteomicsPublishingRecombinant ProteinsResearchRoleSerineSerine/Threonine PhosphorylationSilicon DioxideSiteStructureTestingTherapeuticThreonineTimeToxic effectWestern BlottingWorkalpha synucleinamyloid formationamyloid structurebasebiophysical propertiesdark matterexperimental studyglycosylationhuman diseasein vivomonomermutantpreventprogramsprotein aggregationprotein functionpublic health relevancestereochemistrysugarsynthetic proteinunnatural amino acids
项目摘要
Modified Project Summary/Abstract (The abstract contained no specific references to the in vivo mouse experiments and therefore is unchanged): O-GlcNAc modification is a dynamic protein-modification that is absolutely required for embryonic development in mammals, and is misregulated in diseases, including diabetes, neurodegeneration and cancer. Although approximately 1,000 proteins are modified by O-GlcNAc, the effects of the vast majority of these modifications on protein function are completely unknown. The long-term goal of our research program is to fill in these missing gaps by determining the biochemical consequences of O-GlcNAc on proteins that are key to human disease. To accomplish this goal, we use a combination of carbohydrate and synthetic protein chemistries to build O-GlcNAc modified proteins for subsequent biological experiments. This chemical approach is uniquely enabling, as it is currently the only way to generate homogeneous and site-specifically O-GlcNAc modified proteins. We have been very successful and have used synthetic proteins to determine that O-GlcNAc has a multifaceted role in preventing the amyloid aggregation of proteins in neurodegenerative diseases. Specifically, we have found that O-GlcNAc both directly inhibits the aggregation of amyloid forming proteins and activates the activity of certain small chaperones. In this proposal we will continue to build on these discoveries. In Aim 1, we will determine how O-GlcNAc inhibits the early stages of α-synuclein amyloid formation. In Aim 2, we will test whether O-GlcNAc alters the structure/toxicity relationships of α-synuclein amyloids. In Aim 3, we examine how O-GlcNAc alters the small heat shock protein interactome. Finally, in Aim 4, we will determine if O-GlcNAc can rescue the activity of mutant chaperones that cause Charcot-Marie-Tooth disease. At the conclusion of these independent aims, we will have further unravelled the mechanisms by which O-GlcNAc inhibits protein aggregation and provided critical data to support the ongoing efforts to target O-GlcNAc therapeutically.
修改后的项目摘要/摘要(摘要未包含体内小鼠实验的具体参考文献,因此未发生变化):O-GlcNAc修饰是哺乳动物胚胎发育绝对需要的动态蛋白质修饰,并且在疾病(包括糖尿病、神经变性和癌症)中失调。虽然大约有1,000种蛋白质被O-GlcNAc修饰,但这些修饰中的绝大多数对蛋白质功能的影响完全未知。我们研究计划的长期目标是通过确定O-GlcNAc对人类疾病关键蛋白质的生化后果来填补这些缺失的空白。为了实现这一目标,我们使用碳水化合物和合成蛋白质化学的组合来构建O-GlcNAc修饰的蛋白质用于随后的生物实验。这种化学方法是独特的,因为它是目前唯一的方法来产生同质和位点特异性O-GlcNAc修饰的蛋白质。我们已经非常成功地使用合成蛋白质来确定O-GlcNAc在预防神经退行性疾病中蛋白质的淀粉样蛋白聚集方面具有多方面的作用。具体地,我们已经发现O-GlcNAc既直接抑制淀粉样蛋白形成蛋白的聚集,又激活某些小分子伴侣蛋白的活性。在本提案中,我们将继续以这些发现为基础。在目标1中,我们将确定O-GlcNAc如何抑制α-突触核蛋白淀粉样蛋白形成的早期阶段。在目的2中,我们将测试O-GlcNAc是否改变α-突触核蛋白淀粉样蛋白的结构/毒性关系。在目标3中,我们研究了O-GlcNAc如何改变小的热休克蛋白相互作用组。最后,在目标4中,我们将确定O-GlcNAc是否可以拯救引起腓骨肌萎缩症的突变分子伴侣的活性。在这些独立目标的结论中,我们将进一步揭示O-GlcNAc抑制蛋白质聚集的机制,并提供关键数据来支持正在进行的治疗靶向O-GlcNAc的努力。
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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Matthew Robert Pratt其他文献
Matthew Robert Pratt的其他文献
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{{ truncateString('Matthew Robert Pratt', 18)}}的其他基金
Chemical Tools for the Investigation and Manipulation of Protein Glycosylation
用于研究和操作蛋白质糖基化的化学工具
- 批准号:
10444494 - 财政年份:2017
- 资助金额:
$ 34.69万 - 项目类别:
Chemical Tools for the Investigation and Manipulation of Protein Glycosylation
用于研究和操作蛋白质糖基化的化学工具
- 批准号:
9695984 - 财政年份:2017
- 资助金额:
$ 34.69万 - 项目类别:
Chemical Tools for the Investigation and Manipulation of Protein Glycosylation
用于研究和操作蛋白质糖基化的化学工具
- 批准号:
10621302 - 财政年份:2017
- 资助金额:
$ 34.69万 - 项目类别:
Chemical Tools for the Investigation and Manipulation of Protein Glycosylation
用于研究和操作蛋白质糖基化的化学工具
- 批准号:
10166867 - 财政年份:2017
- 资助金额:
$ 34.69万 - 项目类别:
Chemical Tools for the Investigation and Manipulation of Protein Glycosylation
用于研究和操作蛋白质糖基化的化学工具
- 批准号:
9422572 - 财政年份:2017
- 资助金额:
$ 34.69万 - 项目类别:
Functional Analysis of O-GlcNAc using Synthetic Protein Chemistry
使用合成蛋白质化学对 O-GlcNAc 进行功能分析
- 批准号:
10298804 - 财政年份:2015
- 资助金额:
$ 34.69万 - 项目类别:
Functional Analysis of O-GlcNAc Modifications Using Synthetic Protein Chemistry
使用合成蛋白质化学对 O-GlcNAc 修饰进行功能分析
- 批准号:
9321152 - 财政年份:2015
- 资助金额:
$ 34.69万 - 项目类别:
Functional Analysis of O-GlcNAc Modifications Using Synthetic Protein Chemistry
使用合成蛋白质化学对 O-GlcNAc 修饰进行功能分析
- 批准号:
9754837 - 财政年份:2015
- 资助金额:
$ 34.69万 - 项目类别:
Functional Analysis of O-GlcNAc using Synthetic Protein Chemistry
使用合成蛋白质化学对 O-GlcNAc 进行功能分析
- 批准号:
10671580 - 财政年份:2015
- 资助金额:
$ 34.69万 - 项目类别:
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