Toll-Like Receptor and Dry Eye Inflammation and Infection

描述（由申请人提供）：干眼症（DES）影响全球7- 33%的人口，是个人寻求眼科护理的主要原因之一。患者会出现慢性眼部不适，角膜溃疡的风险增加。尽管其常见，但引发炎症的病理生理学仍然困扰着许多临床医生和研究人员，使得DES难以治疗和管理。先前的研究表明，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）的产生，因此破坏眼表。引发这种炎症的机制尚不清楚，是新型治疗干预的主要目标。来自我的实验室和现在其他实验室的数据表明的一种机制是，Toll样受体（TLR）通过刺激促炎细胞因子和MMP的产生而参与DES炎症，促炎细胞因子和MMP响应于来自应激诱导分子的损伤相关分子模式（DAMP）或来自完整或降解微生物的病原体相关分子模式（PAMP）。另一方面，由于TLR刺激针对入侵病原体的先天性免疫应答，当眼表面因干燥而受损时，它们还可以通过产生抗菌肽（AMP）减少微生物定植来发挥保护作用。这种情况与DES的临床表现一致，因为伴随微生物感染不常见。由于这些原因，研究TLR在DES中的作用是必要的，并且可能导致开发用于治疗DES和微生物感染的新治疗选择。该提议的中心假设是，干眼中的眼表面上的DAMP增加，并且可以激活TLR以增加破坏性促炎细胞因子和MMP的产生，同时还通过产生AMP来增强病原体保护。这一假设将通过以下具体目标进行检验。具体目标1将检查DES和DES相关疾病中DAMP的参与情况。具体目标2将研究TLR对实验性干眼（EDE）小鼠和人眼表细胞中促炎细胞因子和MMP分泌的影响。具体目标3将确定TLR参与调节EDE小鼠的微生物感染风险。随着DES的患病率预计在未来几十年内翻一番，缺乏明确的治疗方案，迫切需要更好地了解DES的病理生理学。这些研究完成后，将确定TLR在DES中眼表炎症和感染中的作用，为DES炎症和感染的病理生物学提供新的见解，这将有助于开发减少炎症同时不增加感染风险的治疗方案。

DESCRIPTION (provided by applicant): 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.