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.

干眼病(DED)是一种常见的疾病，可导致不适并对视觉质量和 生活质量。DED的许多亚型与眼表炎症有关。食道发炎 眼表面是由先天免疫系统和获得性免疫系统共同调节的。DED的炎症可以是 与眼部疼痛有关。混合性DED(MDE)的特征是泪液产量减少(含水 和更多的泪膜蒸发(蒸发性干眼)。MDE通常出现在后期阶段。 是DED的。退伍军人中的DED很常见，可能与比 平民。退伍军人有患MDE的风险，因为多次用药和合并疾病的比率很高 疾病，如青光眼、创伤后应激障碍和抑郁症。目前的治疗方案是 有限度的，而且主要是缓解。通过以下方式改善退伍军人的生活质量大有可为 开发治疗DED炎症的新方法。免疫系统的一个区域一直是 DED的治疗学对先天免疫系统的研究不足，也缺乏针对性。尤其是收费式 受体(TLR)信号通路在DED中可能过度活跃。组蛋白是一类主要发现的多肽 在唾液中，已知具有显著的伤口愈合和抗菌性能。几乎没有数据存在于 组蛋白多肽的作用机制。我们发现，组蛋白多肽可以改善人的健康 在模拟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类治疗药物，针对先天性免疫系统，以减少眼表炎症。我们的 中心假设是，组蛋白多肽可以改善过度活跃的先天组织的损伤效应。 DED中的免疫信号。我们将利用一个经过良好审查的MDE模型来展示组蛋白的有效性 多肽在治疗DED中的作用。我们还将进行机制研究，以寻找组织蛋白的关键调节因子 多肽对眼上皮细胞天然免疫途径的影响。这项拟议的研究具有创新性，因为它是 首次研究使用组蛋白多肽作为治疗MDE先天免疫过度的方法。 我们相信，这些研究的结果将在新疗法的开发方面取得重大进展。 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。