Innovative Therapeutic Targets for Fungal Keratitis

真菌性角膜炎的创新治疗靶点

基本信息

批准号：
8926443
负责人：
Eric Pearlman
金额：
$ 22.71万
依托单位：
UNIVERSITY OF CALIFORNIA-IRVINE
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：
2014-09-30 至 2018-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8926443
关键词：
Adverse effects Amphotericin B Antifungal Agents Antineoplastic Agents Antioxidants Aspergillus Binding Biochemical Pathway Biological Assay Blinded Caring Categories Cell membrane Clinical Clinical Trials Collaborations Combined Modality Therapy Contact Lenses Cornea Corneal Injury Corneal Ulcer Data Developed Countries Developing Countries Disease Disease Outbreaks Drug Combinations Drug Targeting Ergosterol Eye Fusarium Growth Hospitals Human Hydroxymethylglutaryl-CoA reductase Hyphae In Vitro Incubated Individual Injection of therapeutic agent Iron Keratitis Keratoplasty Life Mediating Microbial Biofilms Modeling Molds Mus Oryctolagus cuniculus Pathway interactions Patients Pharmaceutical Preparations Phase I Clinical Trials Production Reporting Research Personnel Risk Factors Siderophores Simvastatin Solutions Testing Therapeutic Thioredoxin Trauma Treatment Failure Work Zinc base clinical application cytotoxicity design fungus healthy volunteer improved in vitro Assay in vivo inhibitor/antagonist innovation killings microbial mutant neutrophil novel novel strategies pathogen peripheral blood phase I trial prophylactic public health relevance research study standard care therapeutic target treatment strategy

项目摘要

DESCRIPTION (provided by applicant): We reported that fungal anti-oxidant pathways and iron binding molecules (siderophores) are essential for hyphal growth in the mammalian cornea (J Clin Invest 2012, PMC3708856; PLoS Pathogens 2013, PMC3534057). We also demonstrated that these pathways can be targeted using the anti-cancer drug PX-12, which inhibits the thioredoxin pathway, and by Simvastatin, which inhibits production of the Aspergillus siderophore TAFC (9, 10). In the current proposal, we also show preliminary data that inhibition of zinc transport impairs growth of Aspergillus hyphae in vitro. Studies outlined in the current proposal will examine PX-12, statins compared with other drugs that target these pathways, and which are either in routine clinical use, or which have gone through Phase I trials and shown to be non-toxic (all are commercially available). We will then combine the most effective compounds using a multi-target approach. In year 1, we will determine the most effective agents in a direct in vitro hyphal killing assay (Aim 1), in an in vitro assay designed to augment hyphal killing by human neutrophils (Aim 2), and in our established murine models of trauma induced and contact lens/biofilm induced fungal keratitis (Aim 3). In the second year, we will complete Aim 3 and based on findings in the murine models, we will examine efficacy in a new rabbit model of contact lens associated fungal keratitis. Amphotericin B or natamycin, as common therapies for fungal keratitis, will also be included, and we will examine cytotoxicity of each dru and combination. These novel approaches target essential pathways of hyphal growth in the cornea, have no anticipated systemic side effects as they are administered topically, and have considerable potential as novel therapies for this important disease.

描述（由申请人提供）：我们报道了真菌抗氧化途径和铁结合分子（铁载体）对于哺乳动物角膜中的菌丝生长至关重要（J Clin Invest 2012，PMC3708856；PLoS Pathogens 2013，PMC3534057）。我们还证明，可以使用抑制硫氧还蛋白途径的抗癌药物 PX-12 和抑制曲霉铁载体 TAFC 产生的辛伐他汀来靶向这些途径 (9, 10)。在当前的提案中，我们还显示了抑制锌转运会损害曲霉菌丝体外生长的初步数据。当前提案中概述的研究将检查 PX-12、他汀类药物与针对这些途径的其他药物的比较，这些药物要么在常规临床使用中，要么已经经过 I 期试验并显示无毒（所有药物均已商业化）可用的）。然后，我们将使用多目标方法组合最有效的化合物。在第一年，我们将在直接体外菌丝杀伤试验（目标 1）、旨在增强人类中性粒细胞杀伤菌丝的体外试验（目标 2）以及我们建立的小鼠创伤模型中确定最有效的药物诱发和隐形眼镜/生物膜诱发的真菌性角膜炎（目标 3）。第二年，我们将完成目标 3，并根据小鼠模型的研究结果，我们将检查隐形眼镜相关真菌性角膜炎的新兔模型的疗效。两性霉素 B 或那他霉素作为真菌性角膜炎的常用疗法也将包括在内，我们将检查每种药物及其组合的细胞毒性。这些新方法针对角膜中菌丝生长的基本途径，由于局部给药而没有预期的全身副作用，并且作为这种重要疾病的新疗法具有相当大的潜力。