R21 Orphan nuclear receptors

描述(由申请人提供)：成孔毒素(PFT)是一种丰富的细菌毒力因子，在许多有问题的病原体的感染中发挥作用，是寻找新的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内传播。宿主细胞反过来使用防御途径来生存和修复细胞膜。除了禁用PFT功能外，PFT靶向策略还可能包括启动或增强主机防御。NR4A家族孤儿核受体是我们发现的新的PFT防御因子，其活性和表达可通过小分子化合物在体外和体内进行调控。我们提出了两个特定的目标，旨在阐明NR4A如何使用多个模型系统防御PFTs和完整病原体的分子机制，并将这一新知识作为一种新的治疗策略，以识别小分子化合物来治疗和预防重要的传染病。

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.