Defining the role of NC1 domain assembly in collagen biosynthesis and collagen associated disorders
定义 NC1 结构域组装在胶原蛋白生物合成和胶原蛋白相关疾病中的作用
基本信息
- 批准号:10679523
- 负责人:
- 金额:$ 4.05万
- 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:2023-04-03 至 2025-04-02
- 项目状态:未结题
- 来源:
- 关键词:AffinityAnabolismBasement membraneBiochemicalBiological AssayBiologyBiotechnologyC-terminalCategoriesCell LineCellsCerebral small vessel diseaseCerebrovascular systemChemicalsClinicalCollagenCollagen DiseasesCollagen Type IVCollectionDefectDiseaseEnvironmentExtracellular MatrixExtracellular SpaceEyeFoundationsFutureGeneticGoalsHomoImpairmentIn VitroKidneyKnowledgeLengthLuciferasesMeasuresMediatingMentorsMethodsMissense MutationModelingMutationN-terminalOsteogenesis ImperfectaPathogenesisPathogenicityPathway interactionsPhenotypePoint MutationProtein BiochemistryProtein EngineeringProteinsProtomerReportingResearchRoleSignal TransductionStructureTestingTherapeuticTissuesWorkbonecell motilitydesigndisease-causing mutationexperienceexperimental studyextracellularinnovationmechanical propertiesmutantprotein protein interactionskillstooltraining opportunitytranslational studytriple helixwhite matter
项目摘要
PROJECT SUMMARY/ABSTRACT
Collagens are essential components of the extra-cellular matrix and basement membranes, where they serve to
bolster tissue integrity, mediate cell migration, and organize signaling. Collagen proteins have three domains:
the C-terminal trimerization domain (CTD/NC1), the collagen domain and the 7S N-terminal domain. Collagens
undergo folding followed by trimerization and collagen triple helix formation in the ER prior to secretion to the
extra-cellular environment. Trimerization of the NC1 domain is the first step in collagen folding and is required
for formation of the collagen triple helix. Mutations in collagens result in severe diseases, such as Osteogenesis
Imperfecta, Alport’s Disease and Cerebral Small Vessel Disease which impair the integrity of bones, kidneys
and blood vessels in the brain and eye respectively. Although many disease-causing mutations in collagens
have been identified, there still is an incomplete understanding of the mechanisms of pathogenesis. The goal
of this proposal is to understand how perturbing the initial trimerization effects the maturation and
biosynthesis of collagen IV. In my first aim, I will develop new cell-based assays to quantify the effect of NC1
domain perturbation on collagen assembly. Specifically, I have developed a split luciferase assay that measures
NC1 domain interactions in isolation and have begun to quantify the effect of pathogenic mutations. Additionally,
I will develop complementary cell lines that express full-length collagen IV, including the most interesting mutants
identified in the split luciferase assays, to better understand the functional consequences of these perturbations.
In my second aim, I have designed point mutations at the NC1 interface, and identified those that increase or
decrease trimer stability. Excitingly, one of these mutations significantly increased NC1 association and
secretion. Together, these studies will reveal the mechanisms of collagen-associated disease and suggest ways
of circumventing them. The major innovation is the application of cutting-edge computational approaches to
design point mutations that probe specific questions about collagen assembly and stability. Together, we expect
these studies to suggest new avenues for the treatment of collagen associated disorders. Finally, these
experiments serve as an exciting training opportunity, providing me with a mentored research experience in inter-
disciplinary, translational studies.
项目总结/文摘
项目成果
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