Fas Ligand Regulation of Ocular Innate Immunity

申请人（申请人）？摘要）：本文提出的研究将： (i)确定膜FasL（mFasL）和可溶性FasL（sFasL）在 眼内嗜中性粒细胞介导的炎症，最重要的是，（ii） 确定sFasL是否可用于下调嗜酸性粒细胞介导的 炎症和预防嗜酸性粒细胞介导眼损伤。初步研究 证明在免疫豁免眼内，mFasL激活中性粒细胞 并启动先天免疫，而sFasL抑制中性粒细胞活化， 防止先天免疫。最引人注目的是sFasL的能力， 阻断mFasL的促炎作用， mFasL在眼内表达相等。拟议的研究将利用 一种直接在角膜内表达DNA的新方法， 在体内，不同形式的FasL诱导的炎症反应 在角膜基质中表达。mFasL和sFasL两者的能力， 直接活化的中性粒细胞将在体外使用基质细胞进行评估 用不同的FasL cDNA转染。最后一组实验将 在体内确定sFasL是否阻断中性粒细胞介导的炎症， 角膜，并阐明，在体外，sFasL阻断的机制， mFasL诱导中性粒细胞活化。我们预计，这些研究将 产生关于FasL如何调节眼睛内炎症的新信息， 可能导致开发新的治疗方法， FasL预防继发于中性粒细胞介导的炎症的眼损伤。

DESCRIPTION (From the Applicant?s Abstract): The studies proposed herein will: (i) determine the roles of membrane FasL (mFasL) and soluble FasL(sFasL) in neutrophil-mediated inflammation within the eye and most importantly, (ii) determine whether sFasL can be used to downregulate neutrophil-mediated inflammation and prevent neutrophil-mediated ocular damage. Preliminary studies demonstrate that within the immune privileged eye, mFasL activates neutrophils and initiates innate immunity, while sFasL inhibits neutrophil activation ad prevents innate immunity. Most compelling though, was the ability of sFasL to block the pro-inflammatory effects of mFasL when both sFasL when both sFasL and mFasL were equally expressed within the eye. The proposed studies will utilize a novel method of expressing DNA directly within the cornea to characterize, in vivo, the inflammatory response induced by the different forms of FasL expressed within the corneal stroma. The ability of both mFasL and sFasL to directly activate neutrophils will be assessed in vitro using stromal cells transfected with the different FasL cDNAs. The final set of experiments will determine, in vivo, whether sFasL blocks neutrophil mediated inflammation in the cornea, and to elucidate, in vitro, the mechanism by which sFasL blocks mFasL induced neutrophil activation. We anticipate that these studies will yield new information as to how FasL regulates inflammation within the eye, and possibly lead to the development of new treatments using the soluble form of FasL to prevent ocular damage secondary to neutrophil mediated inflammation.