PAR-1b in Integrin Localization and Laminin-111 Assembly in the Salivary Gland

描述（由申请人提供）：几乎每个哺乳动物器官周围都有一种特殊形式的细胞外基质（ECM），称为基底膜。在小鼠下颌下腺（SMG）（一种常用的组织发育模型）中，位于最外层上皮细胞下面的基底膜（BM）对于组织组织结构和功能至关重要。我们最近发现，组织和周围的SMG BM蛋白的表达是由PAR-1b，一个广泛研究的极性蛋白控制。基底膜的表达减少或错误组装已被证明会显著破坏相邻上皮细胞的极化。地下室的破坏 膜也出现在干燥综合征等疾病中。Sj？格伦氏综合征是一种自身免疫性疾病，其影响外分泌腺，包括唾液腺和泪腺，减少分泌产物（唾液和眼泪）并导致患者生活质量的显著降低。在唾液腺中，唾液产物的定向分泌在很大程度上依赖于协调的细胞极性，我们以前已经证明这是依赖于基底膜。我们还表明，为上皮细胞提供包被有基底膜蛋白层粘连蛋白-111的人工基质也增强了细胞极性。细胞极性也依赖于细胞表面受体，如整联蛋白和肌营养不良蛋白聚糖，它们与BM直接接触，并经常传递由外向内的信号。我假设PAR-1b调节细胞表面受体定位到基底细胞表面，这反过来又调节层粘连蛋白-111在基底膜中的组装。此外，我假设在干燥综合征中，细胞极性的破坏可能导致基底膜的破坏。本研究的主要目的是：（1）确定整合素<$3、<$6和<$1和肌营养不良蛋白聚糖的定位是否受PAR-1b激酶活性的控制，（2）确定整合素<$3、<$6和<$1是否受PAR-1b激酶活性的控制，（3）确定整合素<$3、<$6和<$1是否受PAR-1b激酶活性的控制，（4）确定整合素<$3、<$6和<$1是否受PAR-1b激酶活性的控制，（5）确定整合素<$3、<$6和<$1是否受PAR-1b激酶活性的控制。1和/或肌营养不良蛋白聚糖调节层粘连蛋白-111在基底膜中的组装，并因此调节唾液上皮细胞的细胞极性，以及（3）确定是否存在与受干燥综合征影响的人类和小鼠唾液腺中基底膜降解相关的这种极性机制的变化。

DESCRIPTION (provided by applicant): Surrounding virtually every mammalian organ is a specialized form of extracellular matrix (ECM) known as the basement membrane. In the mouse submandibular salivary gland (SMG), a commonly used model for tissue development, the basement membrane (BM), underlying the outermost epithelial cells, is critical for tissue organization and function. We have recently shown that the organization and expression of BM proteins surrounding the SMG is controlled by PAR-1b, a widely studied polarity protein. Decreased expression or misassembly of the basement membrane has been shown to significantly disrupt the polarization of the adjacent epithelial cells. Disruption of the basement membrane has also been seen in diseases such as Sj¿gren's syndrome. Sj¿gren's syndrome is an autoimmune disease that affects the exocrine glands, including the salivary glands and the lacrimal glands, decreasing secretory products (saliva and tears) and causing significant decreases in the patient's quality of life. In the salivary gland, directional secretion of salivar products relies heavily on coordinated cellular polarity, which we have previously shown to be dependent on the basement membrane. We have also shown that providing epithelial cells with an artificial matrix coated with the basement membrane protein laminin-111 also enhances cellular polarity. Cellular polarity is also dependent upon cell surface receptors such as integrin and dystroglycan that make direct contacts with the BM and frequently relay outside-in signals. I hypothesize that PAR-1b regulates the localization of cell surface receptors to the basal cell surface, which in turn regulates the assembly of laminin-111 in the basement membrane. Further, I hypothesize that in Sj¿gren's syndrome, disruption of cellular polarity may lead to disruption of the basement membrane. The main goals of this research are: (1) to determine whether the localization of integrins ¿3, ¿6, and ¿1 and dystroglycan is under the control of PAR-1b kinase activity, (2) to determine whether integrin ¿3, ¿6, and ¿1 and/or dystroglycan regulate the assembly of laminin- 111 in the basement membrane and therefore the cellular polarity of the salivary epithelial cells, and (3) to determine whether there is a change in this proposed polarity mechanism associated with degraded the basement membrane in human and mouse salivary glands affected by Sj¿gren's syndrome.