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

项目摘要 本提案的目的是研究抗炎和促消退蛋白的具体作用 膜联蛋白A1（AnxA 1）在干燥综合征（SjS）的发展和发病过程中， 主要针对唾液腺和泪腺的风湿性疾病，导致临床上的眼干和口干 症状SjS的病理生理事件与异常蛋白水解密切相关。该提案 假设SJS相关的蛋白水解加工改变了抗炎和促消退特性， AnxA1尽管AnxA 1的缺失与不受控制的增殖和自身反应性免疫缺陷的激活有关， Th 17细胞在实验性自身免疫性葡萄膜炎小鼠模型中的作用， AnxA 1在SjS病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， AnxA 1的区域，具有AnxA 1抗炎特性的主要药效团。目标1将 确定用N-末端AnxA 1肽ac 2 -26进行预防性治疗是否会减轻炎症， 在NOD小鼠模型中调节T细胞应答并防止唾液腺破坏。目标2将评估 AnxA 1保护性蛋白酶抑制剂对NOD小鼠SjS发展和发病的影响。结果 这项研究将提供关键的见解AnxA 1在调节自身免疫反应的作用， 促进SjS的解决，并提出新的机制衍生的诊断和控制策略 炎症和组织功能障碍和破坏。

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.