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Novel Cell-in-Gel System for Mechanotransduction Study at the Single Cell Level

用于单细胞水平机械转导研究的新型凝胶细胞系统

基本信息

批准号：
9118367
负责人：
Ye Chen-Izu
金额：
$ 39.17万
依托单位：
UNIVERSITY OF CALIFORNIA AT DAVIS
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-08-01 至 2019-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9118367
关键词：
3-Dimensional Arrhythmia Avidin Biochemical Reaction Biological Biology Biomedical Engineering Blood Circulation Cardiac Myocytes Cardiomyopathies Cell surface Cells Chemistry Complex Computer software Contracts Data Defect Devices Diastole Dilated Cardiomyopathy Dystroglycan Dystrophin Engineering Environment Focal Adhesions Functional disorder Gel Glass Glycoproteins Goals Health Heart Heart Diseases Heart failure Hydrogels Hypertension Image Integrins Lead Life Masks Measures Mechanical Stress Mechanics Molecular Molecular Target Molecular and Cellular Biology Muscle Muscle Cells Muscular Dystrophies Mutation Myocardial dysfunction Myocardium Pathway interactions Pharmaceutical Preparations Pharmacotherapy Polymers Proteins Role Scientist Signal Pathway Signal Transduction Stress Stretching Structural Genes Synthesis Chemistry System Systole Talin Techniques Technology Testing Time Vinculin base blood pump carbon fiber cell type crosslink effective therapy experience hemodynamics in vivo innovation mathematical model meetings mouse model new technology novel pressure protein complex research study response retinal rods shear stress tool

项目摘要

DESCRIPTION (provided by applicant): The heart senses the changing mechanical load and adjusts the contractile strength, on a beat-to-beat basis, to match the load in order to effectivel pump blood into circulation. High blood pressure often leads to arrhythmias and heart diseases. Defects in structural proteins, such as in muscular dystrophy, can also lead to cardiomyopathy. How do the cardiomyocytes sense and respond to mechanical forces? What molecules serve as mechanosensors? What are the signaling pathways that transduce mechanical stress to biochemical reactions in the cell? All these important questions need to be answered by investigating the mechano-chemo- transduction (MCT) mechanisms at cellular and molecular levels. A major hindrance to studying MCT mechanisms is a lack of technology to achieve two important capabilities: one is to control mechanical stress at the single cell level in 3-D environment mimicking the myocardium; the other is to tug on specific cell-surface mechanosensors during myocyte contraction in order to interrogate their role in MCT. However, all currently available techniques come short of having both capabilities. In this project, the PI and her interdisciplinary team will combine synthetic chemistry, muscle mechanics, and cellular and molecular biology to achieve two major goals: one is the bioengineering goal to develop an innovative `Cell-in-Gel' system that have the above two capabilities; the other is the scientific goal of using the new tools to investigate the MCT mechanisms during cardiomyocyte contraction under mechanical load. The Cell-in-Gel system has two major advantages over existing techniques (stretching cells using carbon fibers or glass rods). (1) Live cardiomyocytes are embedded in a 3-D hydrogel (elastic matrix composed of crosslinking polymers) so they experience 3-D mechanical stresses (longitudinal tension, transverse compression, shear stress) during contraction, mimicking the in vivo environment. (2) The gel chemistry allows tethering specific cell-surface mechanosensors (e.g. dystroglycans, integrins) to the gel matrix to impose mechanical stress on them during cell contraction. The Cell-in-Gel system will enable scientists to study MCT complexes, their downstream signaling, and functional consequences in live cardiomyocytes and other cell types. We will test the central hypothesis that two major MCT complexes in cardiomyocytes-the dystrophin-glycoprotein complex (DGC) and the vinculin-talin-integrin complex (VTI)- transduce mechanical stress to modulate the Ca2+ signaling system on a beat-to-beat basis, which enhances Ca2+ transient and contractility in response to mechanical load, but this same mechanism can also cause Ca2+ dysregulation under excessive load. Resolving this MCT mechanism is fundamental to understanding how the heart responds to mechanical load to autoregulate contractility, how excessive loads cause heart diseases, and how DGC mutations in muscular dystrophy lead to Ca2+ dysregulation and cardiac dysfunction.