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.

该副本是利用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这不一定是调查员的机构。 该建议旨在了解α7Beta1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。 α7BETA1整合素和肌营养不良蛋白糖蛋白复合物将肌肉细胞连接到其周围基质。 Duchenne肌肉营养不良（DMD）患者和MDX小鼠（人类疾病的模型）具有基因突变，导致缺乏肌营养不良蛋白。 DMD的特征是进行性肌肉无力导致心肺衰竭早期死亡。 DMD 患者表现出是由于平滑肌细胞附着弱，收缩反应不良和手术后出血过多引起的血管异常。在DMD患者和MDX小鼠的骨骼肌中，α7Beta1integrin增加了，可能会部分补偿缺乏肌营养不良蛋白复合蛋白。骨骼肌中α7BETA1整联蛋白的转基因表达增强了寿命并降低严重营养不良小鼠的病理，从而支持α7beta1和肌营养不良蛋白在功能上重叠的假设。肌营养不良蛋白和α7BETA1整联蛋白均在血管平滑肌中表达，它们介导细胞附着层粘连蛋白。肌营养不良蛋白复合物参与血管平滑肌可塑性和Ca2+稳态。该建议将检验以下假设：α7Beta1整合素在调节血管平滑肌细胞可塑性中具有互补作用。我们将使用MDX小鼠确定在没有肌营养不良蛋白的情况下血管平滑肌中α7BETA1水平是否升高。我们将进一步确定α7Beta1整联蛋白水平是否改变导致Ca2+稳态，细胞收缩力，血管张力和细胞分化的改变。整联蛋白下游的分子将进行分析，以确定增加α7Beta1补偿肌营养不良蛋白的机制。 α7BETA1整合素可能在血管可塑性和疾病中起关键作用，这些研究可能会揭示血管功能的基本分子基础。