Role of Toll-Like Receptors in Bacterial Keratitis

Toll 样受体在细菌性角膜炎中的作用

• 批准号: 6844801
• 负责人: LINDA D HAZLETT
• 金额: $ 37.75万
• 依托单位: WAYNE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-01-01 至 2007-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6844801
• 关键词: CD14 molecule; Pseudomonas aeruginosa; biological signal transduction; cell line; cornea; cytokine receptors; defensins; enzyme linked immunosorbent assay; eye infections; genetically modified animals; immune response; immunoregulation; interleukin 1; keratitis; laboratory mouse; leukocyte activation /transformation; macrophage; messenger RNA; monoclonal antibody; neutrophil; protein localization; protein structure function; receptor expression; toll like receptor

DESCRIPTION (provided by applicant): Pseudomonas aeruginosa (P. aeruginosa) is a common organism associated with bacterial keratitis, especially in extended wear contact lens users. In the United States, the incidence of microbial keratitis is 25,000-30,000 cases annually with cost of treatment estimated at $15-30 million, making the disease of considerable medical and economic impact. In the studies proposed, we will test the overall hypothesis that Toll-like receptor/interleukin-1 receptor (TLR/IL-IR) and their associated molecules (e.g., CD14) play a critical role in the initial (innate) immune response in the cornea and are responsible for the disparate outcome to P. aeruginosa infection of B6 and BALB/c mice. No other laboratory is studying the role of this family of receptors in the eye using a bacterial (non-sterile) keratitis model. Three aims are proposed that will test the hypotheses that: 1) expression levels/distribution of TLR/IL-1Rs (TLR-4, -9, ST2 and SIGIRR) and related molecules (CD14, MD2) in epithelium and stroma are disparate in B6 and BALB/c mice in normal and/or P. aeruginosa infected cornea; 2) the TLR/IL1-R MyD88 vs. TRIF signaling pathway is preferentially activated in susceptible vs. resistant mice after bacterial infection; and 3) adaptive immunity (Th1 vs. Th2 responsiveness) is regulated disparately by TLR/IL-1Rs and their signaling molecules in the infected cornea of B6 vs. BALB/c mice. Thus, the goal of the studies proposed in this application is to elucidate the role of TLR/IL-1R in the innate and adaptive immune response to experimental P. aeruginosa corneal infection resulting in corneal perforation (B6) vs. healing (BALB/c). In the proposed studies, multiple approaches will be used and include use of both in vivo and in vitro models to test TLR expression levels, distribution, signaling and immunoregulatory properties. It is expected that the findings will reveal potential targets for early intervention and/or treatment of P. aeruginosa keratitis.

描述（由申请人提供）： 铜绿假单胞菌（P. aeruginosa）是一种与细菌性角膜炎相关的常见微生物，尤其是在长期佩戴隐形眼镜的使用者中。在美国，微生物性角膜炎的发病率每年为 25,000-30,000 例，治疗费用估计为 15-3000 万美元，使得该疾病产生了相当大的医疗和经济影响。在提出的研究中，我们将检验总体假设，即 Toll 样受体/白细胞介素 1 受体 (TLR/IL-IR) 及其相关分子（例如 CD14）在初始（先天）免疫反应中发挥关键作用。角膜并导致 B6 和 BALB/c 小鼠铜绿假单胞菌感染的不同结果。没有其他实验室使用细菌（非无菌）角膜炎模型来研究该受体家族在眼睛中的作用。提出了三个目标来检验以下假设：1）上皮和间质中 TLR/IL-1R（TLR-4、-9、ST2 和 SIGIRR）和相关分子（CD14、MD2）的表达水平/分布是不同的。 B6 和 BALB/c 小鼠正常和/或铜绿假单胞菌感染的角膜； 2) 细菌感染后，易感小鼠与耐药小鼠相比，TLR/IL1-R MyD88 与 TRIF 信号通路优先激活； 3) B6 与 BALB/c 小鼠受感染角膜中的 TLR/IL-1R 及其信号分子对适应性免疫（Th1 与 Th2 反应性）的调节不同。因此，本申请中提出的研究的目的是阐明TLR/IL-1R在对导致角膜穿孔(B6)与愈合(BALB/c)的实验性铜绿假单胞菌角膜感染的先天性和适应性免疫反应中的作用。 ）。在拟议的研究中，将使用多种方法，包括使用体内和体外模型来测试 TLR 表达水平、分布、信号传导和免疫调节特性。 预计这些发现将揭示早期干预和/或治疗铜绿假单胞菌角膜炎的潜在目标。