Allosteric control of collagen fibril degradation by matrix metalloprotease-1
基质金属蛋白酶-1 对胶原原纤维降解的变构控制
基本信息
- 批准号:10853496
- 负责人:
- 金额:$ 31.4万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-09-20 至 2026-07-31
- 项目状态:未结题
- 来源:
- 关键词:Active SitesAffectAllosteric SiteAnimalsAtherosclerosisBindingBiochemicalBiological AssayBuffersCatalysisCatalytic DomainCause of DeathCellsCollagenCollagen FibrilCollagen Type ICommunicationComplementDiseaseDistantDrug usageDyesExtracellular MatrixFamilyFibrillar CollagenFluorescence Resonance Energy TransferFluorescent DyesGelatinase AGoalsHealthHemopexinHomeHumanHuman bodyImageImmobilizationIndividualInflammationInvadedKineticsLabelLeadLearningLigand BindingLigandsLocationMMP9 geneMapsMeasuresMetalloproteasesMethodsMolecular ConformationMorphologyMotionMutationNeoplasm MetastasisOrganPathologicPathologic ProcessesPhysiologicalPlayPneumoniaProteinsProteolysisPublic HealthRelaxationResistanceResolutionRoleScanning Electron MicroscopySiteSpecificityStructureSurfaceTemperatureTestingTetracyclinesTherapeuticTimeTissuesVariantWaterWeightexperimental studyfluorescence microscopegel electrophoresisimprovedin vitro Assayinhibitorinnovationmembermolecular dynamicsmonomermutantpublic health relevancereconstitutionscaffoldscreeningself assemblyside effectsimulationsingle moleculeskin disordersmall moleculetherapeutic targettriple helixwound
项目摘要
Project Summary
Collagen, the most abundant human protein, provides a scaffold for cells to maintain tissue and organ integrity.
Fibrillar collagen is highly resistant to proteolysis and is degraded by specific matrix metalloproteases (MMPs).
The degradation of fibrillar collagen is an essential part of tissue remodeling and is involved in many normal and
pathological processes. While the degradation of triple-helical collagen monomers is well-studied, degradation
of native collagen fibrils remains poorly understood. Fibrils are insoluble in physiological buffers, heterogeneous,
and extended substrates, making them challenging to study using standard biochemical assays. We have
overcome these limitations by developing a single-molecule method to track and analyze the motion of labeled
MMPs on fibrils using a home-built total internal reflection fluorescence microscope (TIRFM). We propose to
study the roles of MMP1 and MMP9 in degrading type-1 collagen fibrils. MMP1 can degrade triple-helical
collagen, whereas MMP9 cannot degrade triple-helical collagen significantly. However, MMP9 is upregulated in
numerous skin diseases, cancer metastasis, wound, inflammation, pneumonia, and atherosclerosis. We propose
to study the mechanism of fibril degradation by two important MMPs by a combination of single-molecule
tracking, innovative analysis, simulations, ensemble assays, and animal studies.
项目摘要
胶原蛋白是人类最丰富的蛋白质,为细胞提供了一个支架,以维持组织和器官的完整性。
原纤维胶原对蛋白水解具有高度抗性,并被特定的基质金属蛋白酶(MMP)降解。
纤维胶原的降解是组织重塑的重要组成部分,并参与许多正常和
病理过程。虽然三螺旋胶原蛋白单体的降解已得到充分研究,但降解
对天然胶原纤维的结构仍知之甚少。原纤维不溶于生理缓冲液,是异质的,
和扩展的底物,使它们具有挑战性的研究使用标准的生物化学测定。我们有
通过开发单分子方法来跟踪和分析标记的运动,
使用自制的全内反射荧光显微镜(TIRFM)观察纤维上的MMP。我们建议
研究MMP 1和MMP 9在降解1型胶原纤维中的作用。MMP 1可降解三螺旋
胶原蛋白,而MMP 9不能显著降解三螺旋胶原。然而,MMP9是上调,
多种皮肤病、癌症转移、创伤、炎症、肺炎和动脉粥样硬化。我们提出
研究两种重要的MMPs通过单分子结合降解纤维的机制,
跟踪、创新分析、模拟、集成分析和动物研究。
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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Susanta Kumar Sarkar其他文献
Susanta Kumar Sarkar的其他文献
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{{ truncateString('Susanta Kumar Sarkar', 18)}}的其他基金
Allosteric control of collagen fibril degradation by matrix metalloprotease-1
基质金属蛋白酶-1 对胶原原纤维降解的变构控制
- 批准号:
10402052 - 财政年份:2022
- 资助金额:
$ 31.4万 - 项目类别:
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