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）：形成孔的毒素（PFT）是丰富的细菌毒力因子，在许多有问题的病原体中在感染中起作用，并且是寻找新型抗菌治疗剂的潜在靶标。 PFTS穿孔宿主细胞膜，使细菌能够逃避免疫系统并在宿主中扩散。宿主细胞又采用了防御途径来生存和修复其细胞膜。除了禁用PFT功能外，靶向PFT的策略还包括启动或增强宿主防御能力。可以通过小型化合物在体外和体内操纵NR4A家庭孤儿核受体的活性和表达。我们提出了两个旨在阐明NR4AS如何使用多个模型系统来抗PFT和完整病原体的分子机制的特定目标，并将这种新知识作为一种新的治疗策略，以识别小型化合物来治疗和预防重要的感染性疾病。