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: 10046282
• 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 2022-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10046282
• 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; 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; Woman; 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; 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）是一种常见的病症，其可引起不适并对视觉质量产生不利影响， 生活质量DED的许多亚型与眼表炎症相关。炎症 眼表的免疫系统由先天性和适应性免疫系统介导。DED中的炎症可以是 与眼部疼痛有关。混合DED（MDE）的特征在于减少的泪液产生（水性）。 不足）和泪膜的更大蒸发（蒸发性干眼）。MDE通常出现在晚期 的DED。DED在退伍军人中很常见，并且可能与更严重的症状负担有关， 平民退伍军人由于多种药物使用率高和合并症， 这些疾病包括青光眼、创伤后应激障碍和抑郁症。目前的治疗方案是 有限的，主要是姑息性的。改善退伍军人生活质量的巨大机会， 开发治疗DED炎症的新方法。免疫系统的一个区域， 先天性免疫系统在DED中未被治疗学充分研究和靶向不足。特别是Toll类 TLR信号通路可能在DED中过度活跃。组胺素是一个肽家族，主要发现于 在唾液中，并且已知具有显著的伤口愈合和抗菌特性。几乎没有关于 组胺素肽的作用机制。我们已经发现，组胺素肽可以改善健康的 模拟DED的实验条件下的眼表。我们的长期目标是开发一种新的 DED是一类靶向先天免疫系统以减少眼表炎症的DED治疗剂。我们 中心假设是，组胺素肽可以减轻过度活跃的先天免疫缺陷的损害作用， DED中的免疫信号传导。我们将利用一个经过严格审查的MDE模型来显示组胺素的疗效。 肽治疗DED。我们还将进行机制研究，以找到组胺抑制素的关键介质 肽对眼上皮细胞先天免疫途径的影响。这项研究是创新的，因为它是 第一个研究使用组胺素肽治疗先天性免疫过度活跃的MDE。 我们相信这些研究的结果将在开发新疗法方面取得重大进展 通过在临床相关的翻译模型中使用严格和明确定义的方法和指标， 疾病