Thymosin beta-4 as an Adjunct Treatment for Bacterial Keratitis

胸腺素 beta-4 作为细菌性角膜炎的辅助治疗

• 批准号: 10586018
• 负责人: Elizabeth Berger
• 金额: $ 38.5万
• 依托单位: WAYNE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-03-01 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10586018
• 关键词: Address; Adrenal Cortex Hormones; Anti-Bacterial Agents; Antibiotic Resistance; Antibiotic Therapy; Antibiotics; Autacoids; Bacteria; Bacterial Model; Biological Models; Blindness; Cell physiology; Cells; Cipro; Ciprofloxacin; Clinical; Combined Modality Therapy; Communicable Diseases; Complement; Cornea; Corneal Diseases; Data; Development; Disease; Disease Outcome; Effector Cell; Emergency Situation; Exhibits; Eye; Eye Infections; Eye diseases; Goals; Health; Hormones; Host Defense; Human; Immune; Immune response; Immunosuppression; In Vitro; Infection; Infiltration; Inflammation; Inflammation Mediators; Inflammatory; Innate Immune Response; Keratitis; Laboratories; Left; Light; Medical; Modality; Modeling; Multi-Drug Resistance; Mus; Outcome; Outpatients; Pathogenesis; Pathway interactions; Patients; Proteins; Pseudomonas aeruginosa; Regulation; Research Design; Resolution; Role; Signal Transduction; Solid; Staphylococcus aureus; Sterility; Steroids; Structure; Techniques; Testing; Therapeutic; Therapeutic Agents; Therapeutic Effect; Transgenic Mice; Treatment Cost; Vision; Visit; Visual; Visual Acuity; bacterial resistance; clinical application; clinical development; corneal epithelial wound healing; design; economic impact; effective therapy; enzyme biosynthesis; healing; human disease; improved; in vivo; in vivo Model; lipid mediator; microbial; mouse model; novel; pathogen; pre-clinical; preclinical study; resistant strain; response; restoration; side effect; thymosin beta(4); wound healing

Project Summary/Abstract Objective/Hypothesis. Microbial keratitis is a rapidly progressing, sight-threatening infection of the cornea. Currently, treatment of microbial keratitis primarily focuses on the pathogen versus the host response. While control of the bacteria is of utmost importance, antibacterial treatment does not guarantee good visual outcome. Treatment with corticosteroids does address the host response to an extent; however, there remains indecision regarding the use of this class of hormones due to the immunosuppressive side effects. We are investigating an endogenous protein, thymosin beta-4 (Tβ4), which can be used as an adjunct to antibiotics to more effectively treat this visually debilitating disease. Our goal is to understand how Tβ4 promotes resolution of inflammation – an aspect of the disease that has yet to be adequately addressed by current treatments. Further, we will determine its clinical applicability as an adjunct therapy against multiple pathogens known to cause microbial keratitis, including multi-drug resistant strains. Given that microbial keratitis results in over 1 million combined office/outpatient and emergency visits annually with the cost of treatment estimated at $175 million per year in the US alone, these studies are relevant to human health and have considerable medical and economic impact. Specific Aims. This proposal intends to: 1) ascertain the mechanisms of Tβ4 on inflammation-resolution and enhanced host defense; and 2) establish the efficacy of Tβ4 as an adjunct treatment with antibiotic for microbial keratitis against multiple pathogens. Study Design. This proposal implements both in vivo and in vitro studies using a number of well- established techniques to examine the mechanistic and therapeutic effects of Tβ4. In vivo studies include use of transgenic mice, and both P. aeruginosa- and S. aureus-induced infections, including clinical isolates that are antibiotic resistant. Further, we extend beyond infectious keratitis and utilize a sterile keratitis model. Restoration of corneal structure and function will be assessed, as well. In vitro studies are designed to complement the in vivo models; all of which focuses on Tβ4's effect on immune-resolution and enhanced host defense, ultimately leading to restoration of corneal structure and function. Impact. Overall, the studies proposed seek to provide preclinical evidence for the development of a novel, potent immunoresolvent exhibiting significant impact on treatment for ocular infectious disease that is devoid of deleterious immunosuppressive side effects.

项目总结/摘要 目标/假设。微生物性角膜炎是一种进展迅速、威胁视力的角膜感染。 目前，微生物角膜炎的治疗主要集中在病原体对宿主的反应。 虽然控制细菌是至关重要的，但抗菌处理并不能保证良好的视觉效果 结果。皮质类固醇治疗在一定程度上解决了宿主反应;然而， 由于免疫抑制的副作用，对于这类激素的使用仍然犹豫不决。 我们正在研究一种内源性蛋白，胸腺素β 4（Tβ4），它可以作为一种辅助手段， 抗生素来更有效地治疗这种视力衰弱的疾病。我们的目标是了解Tβ4 促进炎症的解决-疾病的一个方面，尚未得到充分解决， 目前的治疗。此外，我们将确定其作为针对多种疾病的辅助治疗的临床适用性。 已知引起微生物角膜炎的病原体，包括多重耐药菌株。鉴于微生物 角膜炎导致每年超过100万的门诊/门诊和急诊就诊， 仅在美国，每年的治疗费用估计为1.75亿美元，这些研究与人类健康有关， 具有相当大的医疗和经济影响。 具体目标。本研究拟从以下几个方面探讨Tβ4的抗炎作用机制 和增强宿主防御; 2）确定Tβ4作为抗生素辅助治疗的有效性， 微生物角膜炎对多种病原体。 研究设计.该提案使用许多良好的方法进行体内和体外研究， 建立技术来检查Tβ4的机制和治疗效果。体内研究包括使用 的转基因小鼠，以及铜绿假单胞菌和S.金黄色葡萄球菌引起的感染，包括 对抗生素有抗药性此外，我们扩展到感染性角膜炎之外，并利用无菌角膜炎模型。 还将评估角膜结构和功能的恢复。体外研究旨在 补充了体内模型;所有这些都集中在Tβ4对免疫消退的影响和增强的免疫反应。 宿主防御，最终导致角膜结构和功能的恢复。 冲击总体而言，提出的研究旨在为开发一种新的， 对眼部感染性疾病的治疗具有显著影响的有效免疫溶解剂， 没有有害的免疫抑制副作用。