Toll-Like Receptor and Dry Eye Inflammation and Infection

Toll 样受体与干眼炎症和感染

• 批准号: 8705526
• 负责人: RACHEL LEIGH REDFERN
• 金额: $ 36.87万
• 依托单位: UNIVERSITY OF HOUSTON
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-01 至 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8705526
• 关键词: Address; Affect; Age; Caring; Cells; Chronic; Clinical; Corneal Ulcer; Data; Desiccation; Development; Dry Eye Syndromes; Endotoxins; Epithelial Cells; Epithelium; Equilibrium; Eye; Film; Functional disorder; Gender; HMGB1 Protein; Heat shock proteins; Human; Immune; Immune response; In Vitro; Individual; Infection; Infection prevention; Inflammation; Invaded; Investigation; Knock-out; Knowledge; Label; Laboratories; Lead; Matrix Metalloproteinases; Messenger RNA; Microbe; Molecular; Molecular Profiling; Mus; Pathogenesis; Pathology; Patients; Pattern; Play; Population; Prevalence; Principal Investigator; Production; Productivity; Proteins; Pseudomonas aeruginosa; Quality of life; Receptor Activation; Research Personnel; Risk; Role; Severities; Staphylococcus aureus; Stress; Surface; Testing; Therapeutic Agents; Toll-like receptors; Wild Type Mouse; antimicrobial peptide; chemokine; corneal epithelium; cytokine; experience; eye dryness; in vivo; insight; killings; mRNA Expression; microbial; microbial colonization; novel therapeutic intervention; novel therapeutics; ocular surface; palliative; pathogen; programs; protein expression; public health relevance; response; therapeutic development; treatment strategy

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.

描述（由申请人提供）：干眼综合症 (DES) 影响着全世界 7-33% 的人口，是个人寻求眼部护理的主要原因之一。患者会经历慢性眼部不适，并且角膜溃疡的风险增加。尽管这种情况很常见，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，泪膜体积的减少会刺激高摩尔压力以及促炎细胞因子和基质金属蛋白酶（MMP）的产生，从而破坏眼表。引发这种炎症的机制尚不清楚，并且是新型治疗干预的主要目标。我的实验室和现在其他实验室的数据表明，Toll 样受体 (TLR) 参与 DES 炎症，其方式是刺激促炎细胞因子和 MMP 的产生，以响应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 会刺激针对入侵病原体的先天免疫反应，因此当眼表因干燥而受损时，它们也可能通过产生抗菌肽 (AMP) 来减少微生物定植，从而发挥保护作用。这种情况与 DES 的临床表现一致，因为伴随的微生物感染并不常见。由于这些原因，研究 TLR 在 DES 中的作用势在必行，并且可能会导致开发出治疗 D​​ES 和微生物感染的新治疗方案。该提案的核心假设是，干眼症患者眼表的 DAMP 增加，可以激活 TLR，增加破坏性促炎细胞因子和 MMP 的产生，同时还通过 AMP 的产生增强病原体保护。该假设将通过以下具体目标进行检验。具体目标 1 将研究 DAMP 在 DES 和 DES 相关病症中的作用。具体目标 2 将研究 TLR 对实验性干眼 (EDE) 小鼠和人眼表细胞促炎细胞因子和 MMP 分泌的影响。具体目标 3 将确定 TLR 在调节 EDE 小鼠微生物感染风险中的作用。由于 DES 的流行率预计在未来几十年内将翻一番，并且缺乏明确的治疗方案，因此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 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而不增加感染风险的治疗方案。