Syndecan-1 in Lung Repair

描述(申请人提供)：肺部经常暴露在环境毒素中。受损的肺上皮必须迅速愈合，才能重新建立身体与外界之间的屏障。许多重塑疾病是异常修复的结果(例如，哮喘重塑、COPD、闭塞性毛细支气管炎、支气管扩张症)。因此，了解肺内正常的修复过程是了解疾病发病机制的基础。损伤后，上皮细胞通过细胞和基质之间的协调反应在创伤表面迁移。肺上皮细胞利用Syndecan-1调节细胞-基质相互作用。Syndecan-1通过在功能上与a2？1整合素偶联，调节细胞与胶原的粘附性，从而实现有效的细胞迁移。初步数据表明，Syndecan-1通过这些蛋白质胞外结构域的直接相互作用来调节a2？1整合素的亲和力状态。此外，整合素构象状态的变化通过改变焦点黏附动力学来控制细胞的迁移速度。该方案的目的是确定Syndecan-1调节a2？1整合素激活状态的机制，从而通过改变焦点黏附动力学来调节细胞迁移。这些研究将通过细胞系、器官型肺上皮细胞培养和体内修复模型进行。目标1将绘制与a2？1整合素相互作用所需的Syndecan-1核心蛋白的特定序列，并确定Syndecan-1和a2？1整合素复合体中的其他结合伙伴。目标2将集中于确定syndecan-1调节1221整合素无限状态的机制。目的3将确定Syndecan-1对a2？1整合素的影响如何调节迁移细胞中的焦点黏附动力学和牵引力。这些研究将更好地确定Syndecan-1通过a2？1整合素激活来调节细胞迁移的机制，并可能确定操纵这种相互作用以调节肺修复的方法。

DESCRIPTION (provided by applicant): The lungs are constantly exposed to environmental toxins. Injured lung epithelium must quickly heal in order to re-establish the barrier between the body and outside world. A number of remodeling diseases are the result of aberrant repair (e.g., asthma remodeling, COPD, obliterative bronchiolitis, bronchiectasis). Therefore understanding the normal reparative process in the lungs is fundamental to understanding the mechanisms of disease pathogenesis. After injury, epithelial cells migrate over the wounded surfaces by a coordinated response between the cell and matrix. The lung epithelium utilizes syndecan-1 in modulating the cell-matrix interaction. By functionally coupling itself to the a2¿1 integrin, syndecan-1 tunes the cell adhesiveness to collagen thereby allowing efficient cell migration to occur. Preliminary data suggests that syndecan-1 is regulating the affinity state of the a2¿1 integrin through a direct interaction of the ectodomain of these proteins. Additionally, changes in the integrin conformational state controls cell migration speed by altering focal adhesion dynamics. The goal of this proposal is to determine the mechanisms by which syndecan-1 regulates the activation state of the a2¿1 integrin thereby modulating cell migration via changes to focal adhesion dynamics. These studies will be performed with cell lines, organotypic lung epithelial cultures and in vivo models of repair. Aim 1 will map the specific sequence of the syndecan-1 core protein needed to interact with the a2¿1 integrin and identify additional binding partners in the syndecan-1 and a2¿1 integrin complex. Aim 2 will focus on identifying mechanisms by which syndecan-1 regulates the 1221 integrin afinity state. Aim 3 will determine how syndecan-1 effects on a2¿1 integrin afinity regulates focal adhesion dynamics and traction forces in migrating cells. These studies will better define the mechanisms by which syndecan-1 regulates cell migration through a2¿1 integrin activation and potentially identify ways to manipulate this interaction to modulate lung repair.