R21 Orphan nuclear receptors

R21 孤儿核受体

• 批准号: 9231663
• 负责人: Adam Jonathan Ratner
• 金额: $ 19.49万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-02-01 至 2018-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9231663
• 关键词: R21; Orphan; nuclear; receptors

DESCRIPTION (provided by applicant): Pore-forming toxins (PFTs) are abundant bacterial virulence factors that play a role in infections by numerous problematic pathogens and are potential targets in the search for novel antimicrobial therapeutics. PFTs perforate host cell membranes, allowing bacteria to evade the immune system and spread within the host. Host cells in turn employ defense pathways to survive and repair their cell membranes. Besides disabling PFT function, PFT-targeting strategies may include the priming or boosting of host defenses. Activity and expression of NR4A-family orphan nuclear receptors, which we have identified as novel PFT defense factors, can be manipulated in vitro and in vivo by small compounds. We propose two specific aims directed at elucidating the molecular mechanisms of how NR4As defend against PFTs and intact pathogens using multiple model systems and at applying this new knowledge as a new therapeutic strategy for identifying small compounds to treat and prevent important infectious diseases.

描述（由申请人提供）：成孔毒素（PFT）是丰富的细菌毒力因子，在许多有问题的病原体感染中发挥作用，并且是寻找新型抗菌疗法的潜在目标。 PFT 穿透宿主细胞膜，使细菌能够逃避免疫系统并在宿主体内传播。宿主细胞反过来利用防御途径来生存和修复其细胞膜。除了禁用 PFT 功能外，PFT 靶向策略还可能包括启动或增强宿主防御。 NR4A 家族孤儿核受体的活性和表达，我们已将其鉴定为新型 PFT 防御因子，可以通过小化合物在体外和体内进行操纵。我们提出了两个具体目标，旨在阐明 NR4As 如何使用多个模型系统防御 PFT 和完整病原体的分子机制，以及应用这一新知识作为新的治疗策略来识别小化合物来治疗和预防重要的传染病。