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

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 本研究试图了解α7β1整合素在调节血管平滑肌可塑性和在血管疾病中的功能作用。整合素α7beta1和抗肌营养不良蛋白糖蛋白复合体将肌肉细胞与其周围的基质连接起来。杜氏肌营养不良症(DMD)患者和MDX小鼠(人类疾病的模型)的基因突变导致肌营养不良蛋白的缺失。DMD的特点是进行性肌肉无力，导致心肺衰竭导致早期死亡。DMD 患者表现出血管异常，原因是血管细胞附着能力弱，收缩反应差，术后出血过多。在DMD患者和MDX小鼠的骨骼肌中，α7β1整合素增加，可能部分弥补了Dstrophin复合体的缺失。α7beta1整合素在骨骼肌中的转基因表达增强，延长了严重营养不良小鼠的寿命，减少了病理改变，支持了alpha7beta1和dystrophin复合体功能重叠的假设。肌营养不良蛋白和α7beta1整合素在血管平滑肌中均有表达，它们介导细胞与层粘连蛋白的附着。抗肌营养不良蛋白复合体参与了血管平滑肌的可塑性和钙稳态。这一建议将检验α7beta1整合素在调节血管平滑肌细胞可塑性方面具有互补作用的假设。我们将使用MDX小鼠来确定在没有dystrophin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钙离子稳态、细胞收缩、血管张力和细胞分化的改变。整合素下游的分子将被分析，以确定增加的α7β1补偿Dstrophin缺失的机制。α7β1整合素可能在血管可塑性和疾病中起关键作用，这些研究可能有助于阐明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.