Syndecan-1 in Lung Repair

Syndecan-1 在肺修复中的应用

基本信息

批准号：
8855470
负责人：
PETER CHEN
金额：
$ 38.2万
依托单位：
CEDARS-SINAI MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-04-07 至 2016-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8855470
关键词：
Adhesiveness Affinity Asthma Beds Binding Bronchiectasis Bronchiolitis Cell Line Cells Chronic Chronic Obstructive Airway Disease Collagen Collagen Type I Complement Complex Core Protein Coupling Data Disease Environment Epithelial Epithelial Cells Epithelium Event Fibrosis Focal Adhesions Generations Goals Guanosine Triphosphate Phosphohydrolases Healed Health In Vitro Infection Inflammation Inflammatory Injury Integrin Binding Integrins Kinetics Lung Malignant Neoplasms Maps Molecular Conformation Neoplasm Metastasis Neutrophil Infiltration PTK2 gene Pathogenesis Pathologic Pathology Periodicity Process Proteins Publishing Regulation Role Signal Transduction Site Speed Surface Tail Talin Therapeutic Toxic Environmental Substances Traction Tumor Cell Invasion Work Wound Healing cell motility healing in vivo in vivo Model injured interstitial lung repair migration prevent repaired response response to injury syndecan wound

项目摘要

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.

描述（由申请人提供）：肺部不断暴露于环境毒素中，受伤的肺上皮必须快速愈合，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。因此，了解肺部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 syndecan-1 调节细胞-基质相互作用，通过功能性地将自身与 a2�1 整合素偶联，syndecan-1 进行调节。细胞对胶原的粘附性允许细胞发生迁移，因此初步数据表明 syndecan-1 通过有效的直接相互作用来调节 a2�1 整合素的亲和状态。此外，整合素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，该提案的目的是确定 syndecan-1 调节 a2�1 整合素激活状态的机制。这些研究将通过细胞系、器官型肺上皮培养物和体内修复模型进行，目标 1 将绘制修复的具体序列。 syndecan-1 核心蛋白需要与 a2�1 整合素相互作用，并识别 syndecan-1 和 a2�1 整合素复合物中的其他结合伙伴。目标 2 将重点确定 syndecan-1 调节 1221 整合素亲和状态的机制。目标 3 将确定 syndecan-1 对 a2�1 整合素亲和力的影响如何调节迁移细胞中的粘着斑动力学和牵引力。将更好地定义 syndecan-1 通过 a2�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。