Novel Treatments for Modulation of Innate Immunity in Veteran Related Eye Diseases

调节退伍军人相关眼病先天免疫的新疗法

• 批准号: 10292904
• 负责人: Vinay Aakalu
• 金额: --
• 依托单位: JESSE BROWN VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-10-01 至 2023-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10292904
• 关键词: Adaptive Immune System; Address; Advanced Development; Affect; Age; Aging; Anti-Bacterial Agents; Anti-Inflammatory Agents; Anxiety; Area; B-Cell Activation; Benzalkonium Chloride; Communities; Complex; Data; Desiccation; Development; Disease; Disease model; Dry Eye Syndromes; Elderly; Elements; Enhancers; Epithelial; Equilibrium; Eye diseases; Family; Female; Film; Functional disorder; Gene Expression; General Population; Genes; Glaucoma; Health; Healthcare; Histidine; Human; IL8 gene; Immune; Immune response; Immune signaling; Immune system; In Vitro; Incidence; Inflammation; Inflammatory; Innate Immune System; Interleukin-1; Interleukin-6; Investigational Therapies; Lead; Light; Lipopolysaccharides; Matrix Metalloproteinases; Mediating; Mediator of activation protein; Mental Depression; Methods; Mitogens; Modeling; Mucositis; Myelogenous; Natural Immunity; Nuclear; Oral; Outcome; Pathway Analysis; Pathway interactions; Patients; Peptides; Pharmaceutical Preparations; Physiological; Post-Traumatic Stress Disorders; Production; Property; Protein Kinase; Proteins; Quality of life; Research; Risk; Risk Factors; Saliva; Salivary; Signal Pathway; Signal Transduction; Stimulus; Symptoms; System; TNF gene; Testing; Therapeutic Agents; Toll-like receptors; Topical application; Toxic effect; Transcription Factor AP-1; Veterans; Vision; Visual; antimicrobial; aqueous; clinically relevant; comorbidity; corneal epithelial wound healing; corneal epithelium; cytokine; effective therapy; efficacious treatment; epithelial wound; evaporation; eye dryness; histatin 1; histidine-rich proteins; improved; in vitro Model; in vivo; in vivo Model; innate immune pathways; innovation; lacrimal; military veteran; mouse model; novel; novel therapeutics; ocular pain; ocular surface; older women; oral biology; p38 Mitogen Activated Protein Kinase; palliative; targeted treatment; therapeutic target; translational model; wound healing

Dry eye disease (DED) is a common condition that can cause discomfort and adversely affect visual quality and quality of life. Many subtypes of DED are associated with ocular surface inflammation. Inflammation of the ocular surface is mediated by both the innate and adaptive immune systems. Inflammation in DED can be associated with ocular pain. Mixed DED (MDE) is characterized by decreased tear production (aqueous deficient) and greater evaporation of the tear film (evaporative dry eye). MDE is often present in later stages of DED. DED amongst Veterans is common, and can be associated with a more severe symptom burden than civilians. Veterans are at risk for developing MDE due to high rates of multiple medication use and co-morbid conditions, like glaucoma, post-traumatic stress disorder and depression. Current treatment options are limited and primarily palliative. Great opportunity exists to improve the quality of life of Veterans by developing novel treatments for inflammation in DED. An area of the immune system that has been understudied and under-targeted by therapeutics in DED is the innate immune system. In particular Toll-like receptor (TLR) signaling pathways may be over-active in DED. Histatin is a family of peptides found primarily in saliva and is known to have significant wound healing and anti-bacterial properties. Little data exist on the mechanisms of action of histatin peptides. We have found that histatin peptides can improve the health of the ocular surface under experimental conditions that mimic DED. Our long term objective is to develop a new class of DED therapeutics that target the innate immune system to reduce ocular surface inflammation. Our central hypothesis is that histatin peptides can ameliorate the damaging effects of an overactive innate immune signaling in DED. We will utilize a well vetted model of MDE in order to show the efficacy of histatin peptides in treating DED. We will also undertake mechanistic studies to find the critical mediators of histatin peptide effects on innate immune pathways in ocular epithelia. The proposed research is innovative as it is the first study to investigate the use of histatin peptides as a treatment for innate immune over-activity in MDE. We believe the results of these studies will yield significant progress in the development of new therapeutics through the use of rigorous and well defined methods and metrics in clinically relevant translational models of disease.

干眼症 (DED) 是一种常见疾病，会引起不适并对视觉质量和视力产生不利影响。 生活质量。 DED 的许多亚型都与眼表炎症有关。炎症 眼表由先天性免疫系统和适应性免疫系统介导。 DED 中的炎症可能是 与眼部疼痛有关。混合 DED (MDE) 的特点是泪液产生减少（房水 缺乏）和泪膜蒸发较多（蒸发性干眼症）。 MDE 通常出现在后期 的DED。干眼症在退伍军人中很常见，并且可能会导致比退伍军人更严重的症状负担 平民。由于多种药物的使用和合并症的发生率较高，退伍军人面临患 MDE 的风险 青光眼、创伤后应激障碍和抑郁症等疾病。目前的治疗方案是 有限且主要是姑息性的。存在改善退伍军人生活质量的绝佳机会 开发针对 DED 炎症的新疗法。免疫系统的一个区域已被 对于 DED 的治疗，我们对先天免疫系统的研究和针对性不足。特别是像Toll一样 受体 (TLR) 信号通路在 DED 中可能过度活跃。组氨酸是主要发现的一个肽家族 存在于唾液中，已知具有显着的伤口愈合和抗菌特性。上存在的数据很少 组蛋白肽的作用机制。我们发现组氨酸肽可以改善人体的健康 模拟 DED 的实验条件下的眼表。我们的长期目标是开发新的 一类针对先天免疫系统以减少眼表炎症的 DED 疗法。我们的 中心假设是组氨酸肽可以减轻过度活跃的先天性损伤的影响 DED 中的免疫信号传导。我们将利用经过严格审查的 MDE 模型来展示组蛋白的功效 肽治疗 DED。我们还将进行机制研究，以找到组蛋白的关键介质 肽对眼上皮先天免疫途径的影响。拟议的研究具有创新性，因为它是 第一项研究使用组蛋白肽治疗 MDE 中的先天免疫过度活动。 我们相信这些研究结果将为新疗法的开发带来重大进展 通过在临床相关的转化模型中使用严格且明确定义的方法和指标 疾病。