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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：
Susanta Kumar Sarkar
金额：
$ 31.4万
依托单位：
ARIZONA STATE UNIVERSITY-TEMPE CAMPUS
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：
https://reporter.nih.gov/project-details/10853496
关键词：
Active Sites Affect Allosteric Site Animals Atherosclerosis Binding Biochemical Biological Assay Buffers Catalysis Catalytic Domain Cause of Death Cells Collagen Collagen Fibril Collagen Type I Communication Complement Disease Distant Drug usage Dyes Extracellular Matrix Family Fibrillar Collagen Fluorescence Resonance Energy Transfer Fluorescent Dyes Gelatinase A Goals Health Hemopexin Home Human Human body Image Immobilization Individual Inflammation Invaded Kinetics Label Lead Learning Ligand Binding Ligands Location MMP9 gene Maps Measures Metalloproteases Methods Molecular Conformation Morphology Motion Mutation Neoplasm Metastasis Organ Pathologic Pathologic Processes Physiological Play Pneumonia Proteins Proteolysis Public Health Relaxation Resistance Resolution Role Scanning Electron Microscopy Site Specificity Structure Surface Temperature Testing Tetracyclines Therapeutic Time Tissues Variant Water Weight experimental study fluorescence microscope gel electrophoresis improved in vitro Assay inhibitor innovation member molecular dynamics monomer mutant public health relevance reconstitution scaffold screening self assembly side effect simulation single molecule skin disorder small molecule therapeutic target triple helix wound

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.

项目总结