Metavinculin Regulation of Cell Cytoskeleton Remodeling in Response to Substrate

Metavinculin 对底物响应的细胞骨架重塑的调节

基本信息

批准号：
8793829
负责人：
Kai Shen
金额：
$ 11.56万
依托单位：
SAVANNAH STATE UNIVERSITY
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：
2015-02-01 至 2018-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8793829
关键词：
Actins Address Age Aorta Binding Biological Assay Blood Vessels Bundling C-terminal Cardiovascular Diseases Cause of Death Cells Centrifugation Collaborations Core Facility Coupling Cues Cytoskeleton Data Development Disease Docking Extracellular Matrix F-Actin Fiber Focal Adhesions Fractionation Goals Hypertension Image Immunofluorescence Immunologic Intervention Knowledge Label Lipids Measurement Mechanics Mediating Mentors Modification Morbidity - disease rate Morphology Muscle Mutate NMR Spectroscopy North Carolina Peptides Phosphatidylinositol 4,5-Diphosphate Phospholipids Population Positioning Attribute Prevention Proteins Public Health RNA Splicing Regulation Relative (related person)Research Residual state Risk Factors Role Sedimentation process Signal Pathway Smooth Muscle Myocytes Solutions Spectrum Analysis Structural Models Structure Tail Testing United States Universities Variant Vascular remodeling Vertebral column Vinculin Work base computer studies crosslink dimer disease diagnosis experience hypertension control improved metavinculin mortality novel prevent public health relevance research study response transmission process

项目摘要

DESCRIPTION (provided by applicant): Cardiovascular diseases are the leading cause of death in the United States, and hypertension is an important risk factor for cardiovascular diseases. Mediated through cell-extracellular matrix contact, or focal adhesion, increased extracellular matrix stiffness causes aorta structural changes, thus contributes to hypertension development. It remains unclear how focal adhesion regulates responses of vascular smooth muscle cells to increased stiffness. The focal adhesion protein vinculin and its muscle specific splice variant metavinculin are the key components for force transmission. Therefore, our long-term research goal is to delineate the mechanism by which vascular smooth muscle cells respond to changes in extracellular matrix stiffness through metavinculin and vinculin. The goal of this proposal is to characterize metavinculin tail structural features important for actin cytoskeleton remodeling upon changes in extracellular matrix stiffness. Our hypothesis is that metavinculin C-terminal hairpin, released upon actin or phospholipid binding, binds toward vinculin tail C-terminal base to form a heterodimer, which is indispensable for bundling actin fibers in vascular smooth muscle cells. This hypothesis will be addressed using a combination of novel experimental and computational approaches with the following Specific Aims: (1) to characterize metavinculin and vinculin distribution in response to changes in substrate stiffness, (2) to determine the effect of metavinculin tail structure modification on the association of vinculin tail with actin and phospholipid, and (3) to determine metavinculin tail solution structur and locate metavinculin residues that are involved in actin induced metavinculin-vinculin heterodimer formation. Upon completion of the proposed work, we expect to define the role of metavinculin-vinculin heterodimer in cell cytoskeleton remodeling and build structural models for the heterodimer. The results of this study will help reveal vascular remodeling mechanism due to increased vascular stiffness and suggest new interventions to prevent hypertension development, and in turn help reduce morbidity, mortality, and disparity in cardiovascular diseases.

描述（由适用提供）：心血管疾病是美国的主要死亡原因，高血压是心血管疾病的重要危险因素。通过细胞 - 细胞基质接触或局灶性粘合剂介导的增加细胞外基质刚度会导致主动脉结构变化，从而有助于高血压发育。尚不清楚局灶性粘合剂如何调节血管平滑肌细胞的反应以增加刚度。局灶性粘合剂蛋白质蛋白及其肌肉特异性剪接变体元素蛋白是力传播的关键组成部分。因此，我们的长期研究目标是描述血管平滑肌细胞对通过metavinculin和vinculin的细胞外基质刚度的变化反应的机制。该提案的目的是表征元环蛋白尾尾的结构特征对于肌动蛋白细胞骨架重塑，对细胞外基质刚度的变化进行了重塑。我们的假设是，在肌动蛋白或磷脂结合时释放的元蛋白C末端发夹与Vinculin Tail C末端碱结合以形成异二聚体，这对于血管平滑肌细胞中的绑定肌动蛋白纤维是必不可少的。该假设将使用新型实验和计算方法与以下特定目的的结合来解决：（1）以响应底物刚度变化来表征元弥体蛋白和质子蛋白的分布，（2）确定元素蛋白尾尾结构修饰的影响，以确定拟南芥的结构与actinavin和phospin的结构，以确定脂肪蛋白和磷脂的结构（3）参与肌动蛋白诱导的荟萃元素元素异二聚体形成。提出的工作完成后，我们希望定义元蛋白 - 元素异二聚体在细胞细胞骨架重塑中的作用，并为异二聚体构建结构模型。这项研究的结果将有助于揭示由于血管僵硬增加而导致的血管重塑机制，并提出了防止高血压发展的新干预措施，进而有助于降低心血管疾病的发病率，死亡率和差异。