Vascular Permeability and Ocular Infections

血管通透性和眼部感染

基本信息

批准号：
8990486
负责人：
Michelle C Callegan
金额：
$ 37万
依托单位：
UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-01-01 至 2016-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8990486
关键词：
Address Affect Anti-Inflammatory Agents Anti-inflammatory Antibiotics Bacillus (bacterium)Bacteria Bacterial Infections Bacterial Model Biological Preservation Blindness Blood Blood Circulation Blood-Retinal Barrier Cells Communicable Diseases Cytotoxin Data Development Diabetes Mellitus Diabetic mouse Disease Effector Cell Endophthalmitis Environment Event Evolution Eye Eye Infections Figs - dietary Genus staphylococcus Goals Health Immune Infection Inflammation Inflammatory Integration Host Factors Klebsiella Mediator of activation protein Modeling Mus Natural Immunity Nature Operative Surgical Procedures Organism Outcome Pathogenesis Permeability Posterior eyeball segment structure Postoperative Period Process Publishing Refractory Regimen Research Retina Retinal Septicemia Severities Staging Staphylococcus aureus Staphylococcus epidermidis Strategic Planning Systemic infection Testing Therapeutic Therapeutic Intervention Time Toxin Treatment Failure Vascular Permeabilities Virulence Vision Work bacterial endophthalmitis base clinically relevant design diabetic fighting migration non-diabetic pathogen prevent targeted treatment therapeutic development treatment strategy

项目摘要

DESCRIPTION (provided by applicant): Endophthalmitis is a sight-threatening infection of the interior of the eye resulting from the introduction of organisms into the posterior segment. Severe endophthalmitis often results in irreversible damage to delicate cells of the retina and explosive intraocular inflammation, ultimately resulting in vision loss. Despite aggressive antibiotic, anti-inflammatory, and surgical treatment, significant vision (if not the eye itself) cn be lost in a short period of time. The regularity of treatment failures highlights the need for beter therapeutics which target the pathogenic mechanisms of disease. Current treatments can sterilize the eye, but fail at limiting damaging inflammation and ignore bacterial products which can be equally as damaging. Our research has focused on the pathogenic mechanisms of Bacillus post-traumatic endophthalmitis (PTE) and, more recently, on new models of Klebsiella and Staphylococcus endogenous endophthalmitis (EE). We have identified a theme common to endophthalmitis caused by these and other pathogens: retinal vascular permeability is an initial and important component of the disease process. This new proposal focuses on vascular permeability during the very early stages in the evolution of bacterial endophthalmitis, when organisms enter the eye and inflammation is initiated. We hypothesize that vascular permeability triggered in PTE and post-operative (POE) bacterial endophthalmitis facilitates influx of inflammatory cells into the posterior segment (Aim 1). We similarly hypothesize that vascular permeability initiated during systemic infection facilitates the entry of organisms into te eye, resulting in EE (Aim 2). In these types of endophthalmitis, the outcome is infection, inflammation, and the potential for vision loss. The underlying mechanisms of retinal vascular permeability leading to cellular and bacterial access into the eye during these different types of endophthalmitis are not clear. However, if these events include identifiable common factors that can be therapeutically targeted, infection and inflammation could be limited, resulting in preservation of vision. The aims to be tested are built upon published and new data in our models of bacterial PTE/POE and new models of bacterial EE, with the goal of deciphering the mechanisms of retinal vascular permeability during endophthalmitis. Current therapies do not consider changes in ocular barrier integrity, a likely precursor event to inflammation in PTE/POE and infection in EE. Published studies on endophthalmitis by us and other groups have not focused on the very early stages of bacterial recognition in the eye prior to overt inflammation, a critical time when the cascades responsible for damaging inflammation could be therapeutically averted. Therefore, the findings from this proposal will provide important and clinically relevant information regarding ocular barrier defense during intraocular infection and identify potential targets for therapeutic intervention that will prevent devastating and blinding effects of the disease.

描述（由申请人提供）：内膜膜是一种威胁性的眼睛内部感染，这是由于将有机体引入后段引起的。严重的内膜炎通常会导致视网膜细胞细胞和爆炸性眼内炎症的不可逆损害，最终导致视力丧失。尽管侵略性抗生素，抗炎和手术治疗，但在短时间内，CN的明显视力（如果不是眼睛本身）。治疗失败的规律性突出了针对疾病致病机制的Beter治疗剂的必要性。当前的治疗方法可以消毒眼睛，但无法限制损害炎症并忽略可能同样有害的细菌产物。我们的研究集中在创伤后内脑菌（PTE）的致病机制上，以及最近的klebsiella和葡萄球菌内源性内源性内植物学（EE）的新模型。我们已经确定了由这些病原体和其他病原体引起的内嗜性炎症常见的主题：视网膜血管通透性是疾病过程的初始和重要组成部分。这项新提案的重点是在细菌性内嗜性的早期阶段，当生物体进入眼睛并启动炎症时。我们假设在PTE和术后（POE）细菌性内膜膜引发的血管通透性促进了炎症细胞的流入后段（AIM 1）。同样，我们假设在全身感染期间启动的血管渗透性促进了生物体进入眼睛，从而导致EE（AIM 2）。在这些类型的内嗜性膜中，结果是感染，炎症和视力丧失的潜力。在这些不同类型的内嗜性内炎期间，导致细胞和细菌进入眼睛的视网膜血管通透性的基本机制尚不清楚。但是，如果这些事件包括可识别的常见因素，这些因素可以是治疗靶向的，则可能会限制感染和炎症，从而保留视力。要测试的目的是建立在我们细菌PTE/POE和细菌EE新模型中的已发表和新数据上的，其目的是破译内膜内膜期间视网膜血管通透性的机制。当前的疗法不考虑眼部屏障完整性的变化，这可能是PTE/POE和EE感染中炎症的前体事件。在明显的炎症之前，美国和其他群体发表了有关美国和其他群体细菌识别的早期阶段的研究，可以在治疗上避免造成伤害炎症的级联反应的关键时间。因此，该提案的发现将提供有关眼内感染期间眼部屏障防御的重要且与临床相关的信息，并确定可以防止疾病毁灭性和盲目作用的治疗干预措施的潜在靶标。