Thymosin beta-4 as an Adjunct Treatment for Bacterial Keratitis

项目摘要/摘要 目标/假设。细菌性角膜炎是一种进展迅速、危及视力的角膜感染。 目前，微生物角膜炎的治疗主要集中在病原体与宿主的反应上。 虽然细菌的控制是最重要的，但抗菌治疗并不能保证良好的视觉 结果。使用皮质类固醇治疗确实在一定程度上解决了宿主的反应；然而， 由于免疫抑制的副作用，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质，胸腺素β-4(Tβ4)，它可以用作 抗生素，以更有效地治疗这种视觉衰弱的疾病。我们的目标是了解Tβ4是如何 促进炎症的消退--这是疾病的一个方面，尚未得到充分的解决 目前的治疗方法。此外，我们将确定其作为治疗多发性硬化症的辅助疗法的临床适用性。 已知可导致微生物角膜炎的病原体，包括多药耐药菌株。鉴于这种微生物 角膜炎每年导致100多万次办公室/门诊部和急诊室就诊，费用为 仅在美国，估计每年的治疗费用就高达1.75亿美元，这些研究与人类健康和 有相当大的医疗和经济影响。 明确的目标。本研究的目的是：1)明确T-β-4的抗炎作用机制 和增强的宿主防御；以及2)建立Tβ4作为抗生素辅助治疗的有效性 针对多种病原体的微生物角膜炎。 研究设计。这一建议实施了体内和体外研究，使用了许多井- 已建立的检测Tβ4机制和治疗效果的技术。体内研究包括使用 转基因小鼠，以及铜绿假单胞菌和金黄色葡萄球菌诱导的感染，包括 对抗生素有抗药性。此外，我们超越了感染性角膜炎，并利用了无菌角膜炎模型。 还将评估角膜结构和功能的恢复情况。体外研究旨在 补充体内模型，重点研究T-β4‘-S对免疫功能的分解和增强作用 宿主防御，最终导致角膜结构和功能的恢复。 冲击力。总体而言，拟议的研究试图为开发一种新的、 有效的免疫解析剂对眼部感染性疾病的治疗有重大影响 没有有害的免疫抑制副作用。

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.