Syndecan-1 in Lung Repair

描述（由申请人提供）：肺部持续暴露于环境毒素。受伤的肺上皮必须迅速愈合，以重建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、闭塞性细支气管炎、支气管扩张）。因此，了解肺的正常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受伤表面上迁移。肺上皮利用多配体蛋白聚糖-1调节细胞-基质相互作用。多配体蛋白聚糖-1通过与α 2 <$1整联蛋白功能性结合，使细胞粘附于胶原蛋白，从而使细胞发生有效迁移。初步数据表明，syndecan-1通过这些蛋白质的胞外域的直接相互作用来调节α 2 <$1整联蛋白的亲和力状态。此外，整联蛋白构象状态的变化通过改变粘着斑动力学来控制细胞迁移速度。本提案的目的是确定syndecan-1调节α 2 <$1整合素活化状态的机制，从而通过改变粘着斑动力学来调节细胞迁移。这些研究将使用细胞系、器官型肺上皮培养物和体内修复模型进行。目的1将绘制与α 2 <$1整联蛋白相互作用所需的syndecan-1核心蛋白的特定序列，并鉴定syndecan-1和α 2 <$1整联蛋白复合物中的其他结合伴侣。目标2将集中于识别多配体蛋白聚糖-1调节1221整合素亲和状态的机制。目的3将确定syndecan-1对α 2 <$1整合素亲和力的影响如何调节迁移细胞中的粘着动力学和牵引力。这些研究将更好地确定syndecan-1通过α 2 <$1整合素激活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.