Regulation of salivary gland inflammation in Sjogren's Syndrome by Annexin 1

项目总结 这项建议的目的是研究抗炎和促分解蛋白的具体作用。 膜联蛋白A1(AnxA1)在干燥综合征(SjS)发生发展中的作用 主要针对唾液腺和泪腺的风湿性疾病，导致临床上眼干和口干 症状。SjS的病理生理事件与异常的蛋白分解密切相关。这项建议 假设SjS相关的蛋白分解过程改变了抗炎和促分解特性 AnxA1的。而AnxA1的丢失与自身反应的不受控制的增殖和激活有关 Th17细胞在实验性自身免疫性葡萄膜炎的小鼠模型中，存在关键的知识缺口 AnxA1在干燥综合征发病过程中的作用。在我们的初步研究中，我们发现了N-末端的切割产物 AnxA1的区域，包含AnxA1抗炎特性的主要药效团。目标1将 确定N-末端AnxA1肽AC2-26预防性治疗是否会减少炎症， 在NOD小鼠模型中调节T细胞反应和防止唾液腺破坏。AIM 2将评估 AnxA1保护性蛋白酶抑制剂对NOD小鼠SjS发生发展的影响结果 这项研究将为AnxA1在调节自身免疫反应和 促进SJS的解决方案，并为诊断和控制提出新的机制衍生策略 SjS的炎症和组织功能障碍及破坏。

PROJECT SUMMARY This objective of this proposal is to examine the specific role of the anti-inflammatory and pro-resolving protein Annexin A1 (AnxA1) during the development and onset of Sjögren's Syndrome (SjS), the second most common rheumatic disease that primarily targets the salivary and lacrimal glands causing clinical dry eye and dry mouth symptoms. Pathophysiological events in SjS are strongly associated with aberrant proteolysis. The proposal hypothesizes that SjS-associated proteolytic processing alter the anti-inflammatory and pro-resolution properties of AnxA1. While loss of AnxA1 has been associated with uncontrolled proliferation and activation of autoreactive Th17 cells in the mouse model of experimental autoimmune uveitis, there is a critical knowledge gap about AnxA1 in the SjS disease process. In our preliminary studies, we discovered cleavage products of the N-terminal region of AnxA1 that harbors the main pharmacophore for the anti-inflammatory properties of AnxA1. Aim 1 will determine whether preventive treatment with N-terminal AnxA1 peptide ac2-26 will reduce inflammation, modulate T cell response and prevent salivary gland destruction in the NOD mouse model. Aim 2 will evaluate the effect of AnxA1-protective protease inhibitors on the development and onset of SjS in NOD mice. Results from this study will provide critical insights into the role of AnxA1 in modulating autoimmune response and promote resolution in SjS and suggest novel mechanism-derived strategies for diagnosis and controlling inflammation and tissue dysfunction and destruction in SjS.