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Post-Synthetic Procollagen Processing in Load-Induced Left Ventricular Remodeling

负荷诱导左心室重构中的合成后原胶原加工

基本信息

批准号：
7737431
负责人：
Amy D Bradshaw
金额：
$ 36.88万
依托单位：
MEDICAL UNIVERSITY OF SOUTH CAROLINA
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-01 至 2011-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7737431
关键词：
Adhesives Anabolism Binding Binding Proteins Binding Sites Biochemistry Cardiac Cardiac Myocytes Cardiovascular system Catheterization Cessation of life Chronic Clinical Collagen Collagen Fibril Complementary DNA Cysteine Deposition Development Diagnosis Echocardiography Equilibrium Extracellular Matrix Extracellular Space Fibrillar Collagen Fibroblasts Functional disorder Heart failure Histology Hospitalization Hypertrophy In Vitro Incidence Infection Integral Membrane Protein Label Lead Left Left Ventricular Remodeling Left ventricular structure Location Measurement Measures Metabolic Mus Mutate Myocardial Patients Play Prevalence Process Procollagen Proline Property Proteins Role Scanning Transmission Electron Microscopy Procedures Series Small Interfering RNA Staining method Stains Structure Techniques Testing Time Transgenic Mice Ventricular Ventricular Remodeling constriction crosslink in vivo light microscopy papillary muscle pressure research study

项目摘要

After biosynthesis within the fibroblast, a procollagen molecule is secreted into the extracellular space where it must undergo a series of very ordered, time sensitive, and location sensitive sequential post-synthetic processing steps in order to become a mature cross-linked insoluble structural collagen fibril. We hypothesized that one fundamental independent mechanism by which chronic pressure overload (PO) increases myocardial fibrillar collagen content, causes the development of abnormal diastolic function and chronic heart failure is an alteration in post-synthetic procollagen processing. This overall hypothesis will be tested using 2 specific aims. Specific Aim 1: determine whether PO changes the balance between procollagen processing into mature cross-linked collagen fibrils vs. procollagen degradation. Specific Aim 2: determine in vitro, using murine primary cardiac fibroblast culture studies, whether a change in SPARC (Secreted Protein Acidic and Rich in Cysteine) expression or procollagen binding results in an isolated change in procollagen processing and fibrillar collagen deposition. PO will be produced by transverse aortic constriction (TAC) in mice. We will examine LV structure & function with echocardiography & catheterization, myocardial function with isolated papillary muscles studies, collagen content, composition and morphometric structure with histology & biochemistry, and procollagen synthesis, procollagen processing, and fibrillar collagen degradation rates with metabolic 14C and 3H proline labeling techniques. The mechanism by which TAC and SPARC alter post-synthetic procollagen processing will be examined using in vitro primary cardiac fibroblast culture studies. Thus, this project will examine whether alteration in SPARC-dependent procollagen processing is a fundamental mechanism by which PO increases myocardial fibrillar collagen content and causes diastolic dysfunction.

在成纤维细胞内进行生物合成后，前胶原分子被分泌到细胞中