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Discovery of Novel Therapeutics for Fungal Pathogens

真菌病原体新疗法的发现

基本信息

批准号：
9393966
负责人：
Kwang S Kim
金额：
$ 20.2万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-12-07 至 2018-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9393966
关键词：
Affect Antifungal Agents Antimicrobial Resistance Biological Blood - brain barrier anatomy Brain Candida albicans Central Nervous System Fungal Infections Central Nervous System Infections Collagen Cryptococcus Cryptococcus neoformans Development Endothelial Cells Epidermal Growth Factor Receptor Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Exhibits Funding Opportunities Gefitinib Human In Vitro Infection Modeling Molecular Weight Morbidity - disease rate Morphology Neuraxis Penetration Pharmacology Phase Property Protein Tyrosine Kinase Resistance Testing Therapeutic Tight Junctions Translational Research Validation base brain endothelial cell cysteinyl-leukotriene glucan synthase in vivo microbial monolayer montelukast mortality new therapeutic target novel novel strategies novel therapeutics pathogen receptor response therapeutic target

项目摘要

Discovery of novel therapeutics for fungal pathogens Abstract Fungal central nervous system (CNS) infection continues be an important cause of mortality and morbidity. Cryptococcus neoformans (C. neoformans) and Candida albicans (C. albicans) represent the important fungal pathogens causing CNS infection. Successful treatment of C. neoformans and C. albicans CNS infection is compromised by development of antimicrobial resistance and limited repertoire of antifungal drugs against resistant C. neoformans and C. albicans infection. This application, submitted in response to RFA-AI-15-054, proposes to develop early stage translational research focused on the discovery and development of novel therapeutics against CNS infection caused by eukaryotic fungal pathogens, C. neoformans and C. albicans. Recent studies have shown that CNS-infecting pathogens exhibit the ability to penetrate the blood-brain barrier, the essential step in the development of CNS infection. Since C. neoformans and C. albicans dissemination to the brain is likely to involve their penetration of the blood-brain barrier, we developed the in vitro blood-brain barrier model with human brain microvascular endothelial cells (HBMEC) to investigate C. neoformans and C. albicans penetration of the blood-brain barrier. The HBMEC monolayer, upon cultivation on collagen-coated Transwell inserts, exhibits morphological and functional properties of tight junction formation and a polarized monolayer, a unique property of the blood-brain barrier endothelial cells. We showed that C. neoformans and C. albicans strains exhibited the ability to penetrate the blood-brain barrier. We hypothesize that targeting C. neoformans and C. albicans penetration of the blood-brain barrier provides a novel approach for discovery of novel therapeutics for fungal CNS infection. This hypothesis is supported by our preliminary identification of montelukast (an antagonist of cysteinyl leukotriene type 1 receptor or CysLT1) and gefitinib (an inhibitor of epidermal growth factor receptor or EGFR) that inhibited C. neoformans and C. albicans penetration of the blood-brain barrier. CysLT1 and EGFR have not been previously recognized for their contribution to fungal CNS infection and represent novel therapeutic targets for C. neoformans and C. albicans CNS infection. Determination and validation of CysLT1 and EGFR for their contribution to C. neoformans and C. albicans penetration of the blood-brain barrier will, therefore, facilitates discovery of novel host-specific therapeutic targets common to C. neoformans and C. albicans, which is consistent with the FOA of RFA-AI-15-054.

发现真菌病原体的新疗法