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Elucidating the role of cardiac myofibroblasts on matrix and vasculature remodeling

阐明心肌成纤维细胞对基质和脉管系统重塑的作用

基本信息

批准号：
10431762
负责人：
EMILY OLSZEWSKI
金额：
$ 4.12万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-05-16 至 2023-05-15
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10431762
关键词：
3-Dimensional Affect Aging Aortic Valve Stenosis Apoptosis Area Arteries Artificial Heart Atomic Force Microscopy Automobile Driving Biochemical Biometry Blood Vessels Cardiac Cardiac Myocytes Cardiovascular Physiology Cause of Death Cells Characteristics Chemical Structure Chemicals Chemistry Collagen Collagen Fiber Confocal Microscopy Contracts Coronary Cues Data Deposition Disease Endothelial Cells Endothelium Engineering Environment Extracellular Matrix Extracellular Space Fibroblasts Fibrosis Freeze Drying Gel Gene Activation Generations Genetic Models Goals Heart Heart Diseases Heart failure Hypertension Hypertrophy Image In Vitro Injury Lectin Left Length Liquid Chromatography Longitudinal Studies MAP2K6 gene Maps Measurement Measures Mechanics Mediating Methods Modeling Molecular Mus Myocardial Infarction Myofibroblast Nature Operative Surgical Procedures Organ Pathway interactions Perfusion Perivascular Fibrosis Phenotype Phosphotransferases Physiological Physiology Preparation Process Property Protein Kinase Proteomics Pump Regulation Role Signal Transduction Stimulus Stress Stretching Structure System Therapeutic Three-Dimensional Image Time Tissues Traction Transgenes Transgenic Mice Vascular remodeling Ventricular Work blebbistatin cell growth cell motility cell type combinatorial coronary fibrosis density experimental study extracellular heart function image reconstruction in vitro Model in vivo in vivo Model interstitial knock-down mathematical model mechanical properties microscopic imaging migration overexpression preservation pressure response scaffold second harmonic tandem mass spectrometry two-photon

项目摘要

In every form of heart disease, the secretion of extracellular matrix (ECM) by activated fibroblasts, or myofibroblasts, results in cardiac fibrosis. Fibrosis impedes compliance and pumping function, ultimately leading to heart failure due to left ventricular dilation and loss of mechanical function. Little is known about endothelial cell and vessel adaptations to the environment or how local mechanics and chemistry impact vessel structure and flow in vivo. Combinatorial fibroblast and ECM mechanical and chemical crosstalk with endothelial cells are unknown. Moreover, in vitro models aiming to assess vascular adaptations to an extracellular environment lack physiologically relevant ECMs and instead provide exogenous ECM components to optimize control of variables. A system for in vivo, cell-specific phenotypic manipulation will allow for controlled perturbations at an organ level while maintaining relevant, native ECM remodeling over time. Thus, I propose to examine transgenic mice with cardiac fibroblast-specific overexpression of a constitutively active mitogen-activated protein kinase kinase 6 (MKK6) to study vascular remodeling with respect to the fibroblasts and the ECM they secrete. These mice were previously shown to develop interstitial and perivascular fibrosis after 16-20 weeks of the MKK6 gene activation without an injury stimulus, serving as an effective model of the interstitial fibrosis preserved across the results of aging, hypertension, aortic stenosis, and other diseases of the heart. Importantly, the remodeling seen in these diseases does not involve a massive loss of cardiomyocytes, as in a myocardial infarction, but rather a conserved fibroblast phenotypic change, an altered extracellular space, and/or restricted vascular flow over time. Similarly, manipulation of the MKK6 pathway allows for overexpression or knockdown of cardiac fibroblast activation, corresponding to increased ECM or the inability to secrete ECM as a response to a stimulus, respectively. First, I propose to study the biochemical, structural, and mechanical properties of the ECM as well as the macro- and microvascular responses to activated, quiescent, and control cardiac fibroblast phenotypes in vivo. Second, three-dimensional vessel-like structures with controlled fibroblasts and ECMs will be engineered as in vitro platforms to define the molecular regulators of vascular remodeling induced by microenvironmental cues. The effects of combined signaling will be resolved by global characterization along with a reductionist method. The goal of this work is to inform heart therapies by providing targets for steering cardiac vascular remodeling.

在各种形式的心脏病中，细胞外基质（ECM）的分泌均被激活