Novel Strategy for Endophthalmitis Drug Targets

描述（由申请人提供）： 眼内炎（眼内炎症）是白内障手术等眼科手术后对视力的严重威胁。在美国，每年进行数百万次白内障手术，预计这些手术的数量将随着人口老龄化而增加，预计眼内炎病例的数量也会随之增加。由于眼内炎病原体的耐药性急剧增加，眼内炎的治疗可能具有挑战性。粪肠球菌引起一种具有破坏性和耐药性的眼内炎，常导致失明。本研究的目的是确定眼内E.粪使用创新的体外眼内炎模型。因为眼睛内部通常是无菌的，入侵的微生物，如大肠杆菌。在眼内炎期间，粪便遇到新环境-该环境是眼内的流体，玻璃体液。由于玻璃体液是大肠杆菌的一个新环境。faecalis，我们推测E.粪肠球菌调节其基因表达以响应玻璃体液，从而在玻璃体液中存活和增殖。E.在玻璃体液中表达的faecalis基因可能影响眼内炎发病机制和患者视力结果，并且这些基因的产物是潜在的药物靶点。具体目标是：1.鉴定E. faecalis基因在体外眼内炎模型中表达。全局基因表达谱将用于鉴定E. faecalis基因对玻璃体液的反应差异调节，特别是那些允许E.粪菌在玻璃体内生存和生长。遗传学技术将为今后的动物模型研究奠定基础，以评估这些基因对实验性眼内炎的贡献。2.设计一个易处理的眼睛营养模型。我们将使用严格的定量分析来确定玻璃体液允许生长环境的关键因素。这些数据将被用来开发一个定义的E。faecalis生长培养基模拟玻璃体液组成，使得特定组分可以被操纵、去除或用药物靶向以解决它们在E.粪菌代谢和毒力。 公共卫生相关性： 眼内炎是一个重要的公共卫生问题，因为这种疾病的严重视觉后果-几乎或完全失明。引起眼内炎的微生物对最后一线抗生素的耐药性是极其令人关注的。这项研究将确定新的药物靶点的抗生素耐药眼内炎微生物E。粪便，可用于阻止眼内炎的破坏性视力结果。

DESCRIPTION (provided by applicant): Endophthalmitis (inflammation inside the eye) is a serious threat to vision following ocular surgical procedures such as cataract surgery. Millions of cataract surgeries are performed per year in the United States and the number of these surgeries is expected to increase with an aging population, with an expected accompanying rise in the number of endophthalmitis cases. Treatment of endophthalmitis can be challenging given the dramatic increase in drug resistance in the etiologic agents of endophthalmitis. Enterococcus faecalis causes an unusually destructive and drug-resistant form of endophthalmitis that often leads to blindness. The goal of this research is to identify new drug targets for intraocular E. faecalis using innovative in vitro endophthalmitis models. Because the inside of the eye is normally sterile, invading microbes such as E. faecalis encounter a novel environment during endophthalmitis-that environment is the fluid inside the eye, the vitreous humor. Because vitreous humor is a novel environment for E. faecalis, we hypothesize that E. faecalis modulates its gene expression in response to vitreous humor in order to survive and proliferate there. E. faecalis genes expressed in vitreous humor likely influence endophthalmitis pathogenesis and patient vision outcomes and products of these genes are potential drug targets. The specific aims are to: 1. Identify E. faecalis genes expressed in an in vitro endophthalmitis model. Global gene expression profiling will be used to identify E. faecalis genes differentially regulated in response to vitreous humor, in particular those genes that allow E. faecalis to survive and grow inside the vitreous. Genetic techniques will lay a foundation for future animal model studies to evaluate the contribution of these genes to experimental endophthalmitis. 2. Design a tractable nutritional model of the eye. We will use rigorous quantitative analysis to define key contributors to the permissive growth environment of vitreous humor. These data will be used to develop a defined E. faecalis growth medium mimicking vitreous humor composition such that specific components can be manipulated, removed, or targeted with drugs to address their role in E. faecalis metabolism and virulence. PUBLIC HEALTH RELEVANCE: Endophthalmitis is an important public health concern because of the severe visual outcomes of this disease-near or complete blindness. Resistance of microbes causing endophthalmitis to last-line antibiotics is of extreme concern. This research will identify new drug targets for the antibiotic-resistant endophthalmitis microbe E. faecalis that can be used to thwart the devastating visual outcomes of endophthalmitis.