COBRE: UNV MED SCH: P1: INTEGRIN REGULATION OF VASCULAR SMOOTH MUSCLE

COBRE：UNV MED SCH：P1：血管平滑肌的整合素调节

• 批准号: 7960564
• 负责人: DEAN J. BURKIN
• 金额: $ 19.32万
• 依托单位: UNIVERSITY OF NEVADA RENO
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7960564
• 关键词: Blood Vessels; Cardiopulmonary; Cell Differentiation process; Cell-Matrix Junction; Cells; Centers of Research Excellence; Cessation of life; Complex; Computer Retrieval of Information on Scientific Projects Database; Disease; Duchenne muscular dystrophy; Dystrophin; Exhibits; Failure; Funding; Gene Mutation; Glycoproteins; Grant; Hemorrhage; Homeostasis; ITGA7 gene; Institution; Integrins; Laminin; Light; Longevity; Mediating; Modeling; Molecular; Mus; Muscle Cells; Muscle Weakness; Operative Surgical Procedures; Pathology; Patients; Play; Regulation; Research; Research Personnel; Resources; Role; Skeletal Muscle; Smooth Muscle; Smooth Muscle Myocytes; Source; Testing; Transgenic Organisms; United States National Institutes of Health; Vascular Diseases; Vascular Smooth Muscle; base; human disease; mdx mouse; response

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. This proposal seeks to understand the functional roles of the alpha7beta1 integrin in regulating vascular smooth muscle plasticity and in vascular disease. The alpha7beta1 integrin and the dystrophin glycoprotein complex connect muscle cells to their surrounding matrix. Duchenne Muscular Dystrophy (DMD) patients and mdx mice (a model for the human disease) have genetic mutations that result in an absence of dystrophin. DMD is characterized by progressive muscle weakness leading to early death from cardiopulmonary failure. DMD patients exhibit vascular abnormalities caused by weak smooth muscle cell attachment, poor contractile responses and excessive bleeding after surgery. In skeletal muscle of DMD patients and mdx mice, the alpha7beta1integrin is increased and may partially compensate for the absence of the dystrophin complex. Enhanced transgenic expression of the alpha7beta1 integrin in skeletal muscle increases the longevity and decreases the pathology of severely dystrophic mice, supporting the hypothesis that alpha7beta1 and the dystrophin complex functionally overlap. Both dystrophin and the alpha7beta1 integrin are expressed in vascular smooth muscle where they mediate cell attachment to laminin. The dystrophin complex is involved in vascular smooth muscle plasticity and Ca2+ homeostasis. This proposal will test the hypothesis that the alpha7beta1 integrin has a complementary role in regulating vascular smooth muscle cell plasticity. We will use mdx mice to determine if alpha7beta1 levels are increased in vascular smooth muscle in the absence of dystrophin. We will further determine if altered levels of the alpha7beta1 integrin result in alterations of Ca2+ homeostasis, cell contractility, vascular tone, and cell differentiation. Molecules downstream of the integrin will be analyzed to determine the mechanisms by which increased alpha7beta1 compensates for the absence of dystrophin. The alpha7beta1 integrin may play a critical role in vascular plasticity and disease and these studies may shed light on the underlying molecular basis of vascular function.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目和 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它不一定是研究者的机构。 该提案旨在了解 α7β1 整合素在调节血管平滑肌可塑性和血管疾病中的功能作用。 α7β1 整合素和肌营养不良蛋白糖蛋白复合物将肌肉细胞与其周围基质连接起来。杜氏肌营养不良症 (DMD) 患者和 mdx 小鼠（人类疾病模型）存在基因突变，导致肌营养不良蛋白缺失。 DMD 的特点是进行性肌肉无力，导致心肺衰竭过早死亡。 DMD 患者表现出因平滑肌细胞附着力薄弱、收缩反应差和手术后出血过多而引起的血管异常。在 DMD 患者和 mdx 小鼠的骨骼肌中，α7β1 整合素增加，可能部分补偿肌营养不良蛋白复合物的缺失。骨骼肌中α7β1整合素转基因表达的增强可延长严重营养不良小鼠的寿命并减少其病理状况，支持α7β1和肌营养不良蛋白复合物功能重叠的假设。肌营养不良蛋白和 α7β1 整合素均在血管平滑肌中表达，它们介导细胞与层粘连蛋白的附着。肌营养不良蛋白复合物参与血管平滑肌可塑性和 Ca2+ 稳态。该提案将检验α7β1整合素在调节血管平滑肌细胞可塑性方面具有补充作用的假设。我们将使用 mdx 小鼠来确定在缺乏肌营养不良蛋白的情况下血管平滑肌中的 alpha7beta1 水平是否增加。我们将进一步确定 α7β1 整合素水平的改变是否会导致 Ca2+ 稳态、细胞收缩性、血管张力和细胞分化的改变。将分析整合素下游的分子，以确定增加的 α7β1 补偿肌营养不良蛋白缺失的机制。 α7β1 整合素可能在血管可塑性和疾病中发挥关键作用，这些研究可能揭示血管功能的分子基础。