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

这个子项目是许多利用 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 该建议旨在了解α 7 β 1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。α 7 β 1整联蛋白和肌营养不良蛋白糖蛋白复合物将肌细胞连接到其周围基质。杜氏肌营养不良症（DMD）患者和mdx小鼠（人类疾病的模型）具有导致肌营养不良蛋白缺失的基因突变。DMD的特征是进行性肌无力，导致心肺衰竭的早期死亡。DMD 患者表现出由平滑肌细胞附着弱、收缩反应差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，α 7 β 1整联蛋白增加，可能部分补偿肌营养不良蛋白复合物的缺失。骨骼肌中α 7 β 1整联蛋白的增强转基因表达增加了严重营养不良小鼠的寿命并降低了其病理学，这支持了α 7 β 1和肌营养不良蛋白复合物在功能上重叠的假设。抗肌萎缩蛋白和α 7 β 1整联蛋白都在血管平滑肌中表达，它们在血管平滑肌中介导细胞与层粘连蛋白的附着。抗肌萎缩蛋白复合物参与血管平滑肌可塑性和Ca 2+稳态。这项提议将检验α 7 β 1整合素在调节血管平滑肌细胞可塑性中具有补充作用的假设。我们将使用mdx小鼠来确定在缺乏抗肌萎缩蛋白的情况下，血管平滑肌中的α 7 β 1水平是否增加。我们将进一步确定α 7 β 1整合素水平的改变是否会导致Ca 2+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α 7 β 1补偿肌营养不良蛋白缺失的机制。α 7 β 1整合素可能在血管可塑性和疾病中起关键作用，这些研究可能揭示血管功能的潜在分子基础。

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.