Role of crystallin racemization and isomerization in cataract
晶状体蛋白外消旋和异构化在白内障中的作用
基本信息
- 批准号:10011819
- 负责人:
- 金额:$ 38.5万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2017
- 资助国家:美国
- 起止时间:2017-09-30 至 2022-08-31
- 项目状态:已结题
- 来源:
- 关键词:Amino AcidsAsparagineAspartateAspartic AcidBiophysicsCataractChemicalsCrystallinsDeuteriumDevelopmentGeneticHumanHydrogenIn VitroLaboratoriesLocationMass Spectrum AnalysisMeasuresModificationMutagenesisNMR SpectroscopyPeptidesPharmaceutical PreparationsPhysiologicalPlayPost-Translational Protein ProcessingProcessPropertyProtein BiosynthesisProtein DenaturationProteinsRecombinantsResearchResolutionRoleSiteStructureTechniquesTestingTimeWorkage relatedagedalpha-Crystallinsdeamidationdrug discoveryexperimental studylenslight scatteringnephelometrynovelpreventprotein aggregationprotein structureprotein structure functionracemizationsynthetic protein
项目摘要
Project Summary
Age-related cataract is associated with extensive deamidation, racemization, and isomerization of crystallins,
the major refractive proteins of the lens. Extensive studies by our laboratories and others have found
deamidation significantly decreases the stability of crystallins with minimal structural perturbations. However,
these deamidation mimics created using mutagenesis did not readily aggregate in vitro. We hypothesize that
this is because they were lacking racemization and isomerization, two modifications accompanying
deamidation that may be more disruptive to crystallin structure than deamidation alone. Unlike deamidation,
these modifications cannot be introduced into crystallins by genetic means. This has prevented studies to
gauge the importance of these additional modifications in age-related cataract. Therefore, the purpose of
these experiments is to create γS-crystallins containing specific sites of physiologically relevant racemized and
isomerized aspartates that result from the age-related deamidation process and determine their effect on
protein structure. The specific aims are to: 1) use synthetic heavy peptide standards and high-resolution mass
spectrometry to determine the relative proportion of different racemized and isomerized aspartates in γS-
crystallin from the insoluble protein of aged cataractous human lenses so that relevant species can be
selected, 2) introduce these racemized and isomerized residues into γS-crystallin using semi-synthetic
processes that have never before been used in the lens field, and 3) examine the result of these modifications
on γS-crystallin structure using protein stability and light scattering measurements, hydrogen/deuterium
exchange mass spectrometry, and nuclear magnetic resonance spectroscopy. These experiments will, for the
first time, critically test the potential impact of age-related racemization and isomerization on crystallin
structure. These results could play an important role in slowing cataract development by developing drugs that
specifically prevent the aggregation and light scatter of racemized and isomerized crystallins in aged lenses.
项目总结
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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{{ truncateString('LARRY L DAVID', 18)}}的其他基金
Role of crystallin racemization and isomerization in cataract
晶状体蛋白外消旋和异构化在白内障中的作用
- 批准号:
9752550 - 财政年份:2017
- 资助金额:
$ 38.5万 - 项目类别:
Role of crystallin racemization and isomerization in cataract
晶状体蛋白外消旋和异构化在白内障中的作用
- 批准号:
9933672 - 财政年份:2017
- 资助金额:
$ 38.5万 - 项目类别:
Role of crystallin racemization and isomerization in cataract
晶状体蛋白外消旋和异构化在白内障中的作用
- 批准号:
10242798 - 财政年份:2017
- 资助金额:
$ 38.5万 - 项目类别:
LINEAR ION TRAP MASS SPECTROMETER: CELL BIOLOGY
线性离子阱质谱仪:细胞生物学
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- 资助金额:
$ 38.5万 - 项目类别:
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