Macrophage Gene Expression in Mucosal Inflammation

描述（由申请人提供）：NOT-OD-09-058 NIH宣布竞争性修订申请的恢复ct基金的可用性。这是对母体R01, 2 R01 DK054452，“巨噬细胞基因表达在粘膜炎症”的竞争性补充应用。它的基础是在母体赠款的支持下获得的大量初步结果，这使该项目进入了一个全新的方向。最近对人类克罗恩病（CD）易感基因的描述强调了先天免疫与肠道微生物群的相互作用是疾病发病机制中的关键事件。具体来说，CD敏感基因CARD15、ATG16L1和IRGM都在宿主-微生物应答中发挥重要作用；包括微生物的感知；产品，抗菌肽的生产，以及细胞内细菌的杀灭。在亲本R01中，特异性Aims 3和4阐明了一种新型IBD小鼠模型中自发发生结肠炎的分子发病机制，该模型是磷脂酰肌醇-3激酶（PI3K） p1104亚基基因工程小鼠突变体。在亲本基金中完成的实验表明，PI3K p110D910A/D910A突变小鼠的巨噬细胞对toll样受体信号反应高度敏感，并且在IL-10等抗炎介质存在时下调炎症反应的能力存在缺陷。虽然这些发现有助于解释我们实验中描述的IL-12/23、Th1和Th17细胞因子介导的慢性肠道炎症，但最近的研究结果也表明，PI3K p110D910A/D910A突变小鼠的巨噬细胞对肠道细菌的杀菌活性减弱。这一意想不到的结果1)表明，该小鼠模型可能为理解人类乳糜病的发病机制提供了重要的试剂，2)开辟了一个全新的研究领域，而这一领域并非最初科学提议的目标之一。因此，我们踏上了与CD直接相关的实验室的新的，重要的科学方向。我们建议在分子水平上表征PI3K p1104亚基如何调节巨噬细胞的杀菌活性。为了实现这些目标，我们建立了新的合作关系，有必要为实验室招募新的人才，以进一步发展专业知识和技术来回答这些问题。

DESCRIPTION (provided by applicant): NOT-OD-09-058 NIH Announces the Availability of Recovery ct Funds for Competitive Revision Applications. This is a competitive supplemental application to the parent R01, 2 R01 DK054452, "Macrophage Gene Expression in Mucosal Inflammation". It is based on abundant preliminary results obtained under the auspices of the parent grant which moves this project into a completely new direction. Recently described of susceptibility genes in human Crohn's disease (CD) highlight innate immune interactions with the enteric microbiota as critical events in disease pathogenesis. Specifically, the CD susceptibility genes CARD15, ATG16L1, and IRGM all have important roles in host-microbial responses; including sensing of microbial; products, production of antimicrobial peptides, and intracellular killing of bacteria. In the parent R01, Specific Aims 3 and 4 elucidate the molecular pathogenesis of spontaneously occurring colitis in a novel mouse model of IBD, genetically engineered mice mutant in the p1104 subunit of phosphatidyl inositol-3-kinase (PI3K). Experiments completed in the parent grant demonstrate that macrophages from PI3K p110D910A/D910A mutant mice are hyper-responsive to toll-like receptor signaling, and defective in their capacity to downregulate inflammatory responses in the presence of anti-inflammatory mediators such as IL-10. Although these findings help explain chronic intestinal inflammation mediated by IL-12/23, Th1, and Th17 cytokines described by our experiments, recent results also show that macrophages from PI3K p110D910A/D910A mutant mice have attenuated bactericidal activity against enteric bacteria. This unanticipated result 1) suggests that this mouse model may provide an important reagent for understanding the pathogenesis of human CD, and 2) leads to an entirely new area of research that was not part of the aims of the original scientific proposal. We therefore embark upon a new, significant scientific direction for the laboratory with direct relevance to CD. We propose to characterize at the molecular level how the PI3K p1104 subunit modulates bactericidal activity in macrophages. To accomplish these aims, we have established new collaborations and it is necessary to recruit new talent to the laboratory to further develop the expertise and technologies to answer these questions. PUBLIC HEALTH RELEVANCE: This supplement will accelerate scientific discovery about the pathogenesis of the human IBDs which affect over 1,000,000 U.S. citizens. This supplement is expected to stimulate the economy by: Enabling increased hours of current part-time staff. The position of the sole support on this project will otherwise be terminated. This will also support experiments in germ- free mice in conjunction with the National Gnotobiotic Rodent Resource Center.