Toll-Like Receptor and Dry Eye Inflammation and Infection

项目摘要 干眼综合征（DES）影响全世界7- 33%的人口，并且是引起干眼综合征的主要原因之一。 个人寻求眼部护理。患者会出现慢性眼部不适， 角膜溃疡尽管其常见，引发炎症的病理生理学仍然 使许多临床医生和研究人员感到困惑，使得DES难以治疗和管理。以前的研究 表明泪膜体积的减少刺激高摩尔压力和 促炎细胞因子和基质金属蛋白酶（MMP），因此破坏眼表面。的 引发这种炎症的机制尚不清楚，但它是新型治疗干预的主要目标。 从我的实验室和现在其他实验室的数据中提出的一种机制是，Toll样受体（TLR） 通过刺激促炎细胞因子和基质金属蛋白酶的产生参与DES炎症， 对来自应激诱导分子或病原体的损伤相关分子模式（DAMP）的反应- 相关的分子模式（PAMP）从完整的或降解的微生物。另一方面，由于TLR 刺激针对入侵病原体的先天免疫应答，它们也可以通过以下方式发挥保护作用： 当眼表面被细菌感染时，通过产生抗微生物肽（AMP）来减少微生物定植， 因干燥而受损这种情况与DES的临床表现一致，因为 伴随的微生物感染是罕见的。由于这些原因，对TLR在DES中的作用的研究 是必要的，并可能导致开发新的治疗选择，用于治疗DES， 微生物感染该建议的中心假设是，DAMP在眼部增加， 干眼表面，并可激活TLR，以增加破坏性促炎因子的产生。 细胞因子和MMP，同时还通过产生AMP增强病原体保护。这 将通过以下具体目标检验这一假设。具体目标1将审查 DES和DES相关条件下的DAMP。具体目标2将研究TLR对 实验性干眼症小鼠和人类促炎细胞因子和MMPs的分泌 眼表细胞具体目标3将确定TLR参与调节微生物感染风险， 用EDE感染小鼠。随着DES的流行预计将在未来几十年内翻一番， 明确的治疗方案，有一个关键的需要，以更好地了解DES的病理生理。在 完成这些研究后，TLR在DES眼表炎症和感染中的作用将被进一步研究。 这为DES炎症和感染的病理生物学提供了新的见解， 开发减少炎症同时不增加感染风险的治疗方案。

Project Summary Dry eye syndrome (DES) affects 7- 33% of the population worldwide and is one of the leading causes for individuals to seek eye care. Patients experience chronic ocular discomfort and have an increased risk for corneal ulceration. Despite its common occurrence, the pathophysiology that initiates inflammation still perplexes many clinicians and investigators making DES difficult to treat and manage. Previous studies suggest that a reduction in the tear film volume stimulates hyperomolar stress and the production of proinflammatory cytokines and matrix metalloproteinases (MMPs), therefore disrupting the ocular surface. The mechanism that initiates this inflammation is unknown and is a prime target for novel therapeutic intervention. One mechanism suggested by data from my laboratory and now others, is that toll-like receptors (TLRs) are involved in DES inflammation by stimulating the production of proinflammatory cytokines and MMPs in response to damage-associated molecular patterns (DAMPs) from stress induced molecules or pathogen- associated molecular patterns (PAMPs) from intact or degraded microbes. On the other hand, since TLRs stimulate an innate immune response against invading pathogens, they may also play a protective role by reducing microbial colonization via the production of antimicrobial peptides (AMPs) when the ocular surface is compromised from desiccation. This scenario is consistent with the clinical presentation of DES, as concomitant microbial infections are infrequent. For these reasons, investigations into the role of TLRs in DES are imperative and may lead to the development of novel therapeutic options for the treatment of DES and microbial infections. The central hypothesis of this proposal is that DAMPs are increased on the ocular surface in dry eye and can activate TLRs to increase the production of damaging proinflammatory cytokines and MMPs while also enhancing pathogen protection through the production of AMPs. This hypothesis will be tested through the following specific aims. Specific aim 1 will examine the involvement of DAMPs in DES and DES-associated conditions. Specific aim 2 will investigate the impact of TLRs on the secretion of proinflammatory cytokines and MMPs in mice with experimental dry eye (EDE) and in human ocular surface cells. Specific aim 3 will determine the involvement of TLRs in modulating the risk for microbial infection in mice with EDE. With the prevalence of DES expected to double over the next few decades and lack of definitive treatment regimes, there is a critical need to better understand the pathophysiology of DES. At the completion of these studies, the role of TLRs in ocular surface inflammation and infection in DES will be identified, providing new insight into the pathobiology of DES inflammation and infection which will aid in the development of therapeutic regimes that reduce inflammation while not increasing the risk for infection.