Novel Strategy for Endophthalmitis Drug Targets

眼内炎药物靶点的新策略

基本信息

批准号：
8142873
负责人：
KELLI LEA PALMER
金额：
$ 4.05万
依托单位：
MASSACHUSETTS EYE AND EAR INFIRMARY
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-09-01 至 2012-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8142873
关键词：
Acute Address Animal Model Antibiotic Resistance Antibiotics Bacteria Bacterial Physiology Blindness Cataract Extraction Complete Blindness Culture Media Data Disease Disease Outcome Drug Delivery Systems Drug resistance Endophthalmitis Enterococcus faecalis Environment Eye Eye Infections Foundations Future Gene Expression Gene Expression Profiling Genes Genetic Techniques Goals Growth Growth Factor In Vitro Inflammation Intestines Invaded Liquid substance Metabolic Metabolic Pathway Metabolism Microbe Modeling Nutritional Operative Surgical Procedures Outcome Pathogenesis Patients Pharmaceutical Preparations Physiology Production Proliferating Proteins Public Health Refractory Research Research Training Resistance Role Sterility United States Virulence Vision Visual Vitreous humor aging population density design effective therapy in vivo innovation novel novel strategies pathogen public health relevance response

项目摘要

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.

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。美国每年进行数百万例白内障手术，随着人口老龄化，这些手术的数量预计会增加，预计眼内炎病例数也会随之增加。鉴于眼内炎病因的耐药性急剧增加，眼内炎的治疗可能具有挑战性。粪肠球菌会引起一种异常具有破坏性和耐药性的眼内炎，通常会导致失明。这项研究的目标是利用创新的体外眼内炎模型来确定眼内粪肠球菌的新药物靶点。由于眼睛内部通常是无菌的，因此诸如粪肠球菌等入侵微生物在眼内炎期间会遇到一个新的环境——该环境就是眼睛内部的液体，即玻璃体液。由于玻璃体液是粪肠球菌的新环境，我们假设粪肠球菌会响应玻璃体液调节其基因表达，以便在那里生存和增殖。玻璃体液中表达的粪肠球菌基因可能影响眼内炎的发病机制和患者的视力结果，这些基因的产物是潜在的药物靶点。具体目标是： 1. 鉴定体外眼内炎模型中表达的粪肠球菌基因。全局基因表达谱将用于识别响应玻璃体液而差异调节的粪肠球菌基因，特别是那些允许粪肠球菌在玻璃体内生存和生长的基因。遗传技术将为未来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. 设计易于处理的眼睛营养模型。我们将使用严格的定量分析来定义玻璃体生长环境的关键贡献者。这些数据将用于开发模拟玻璃体液成分的明确粪肠球菌生长培养基，以便可以操纵、去除特定成分或用药物靶向特定成分，以解决其在粪肠球菌代谢和毒力中的作用。公共卫生相关性：眼内炎是一个重要的公共卫生问题，因为这种疾病会导致严重的视力后果——接近或完全失明。引起眼内炎的微生物对最后一线抗生素的耐药性令人极为担忧。这项研究将确定针对抗生素耐药性眼内炎微生物粪肠球菌的新药物靶点，可用于阻止眼内炎造成的破坏性视觉后果。