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资金可用性。这是对亲本R 01，2 R 01 DK 054452，“巨噬细胞基因在粘膜炎症中的表达”的竞争性补充申请。它是基于丰富的初步成果下取得的赞助下，家长赠款这将这个项目进入一个全新的方向。 最近描述的人类克罗恩病（CD）的易感基因强调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。具体而言，CD易感基因CARD 15、ATG 16 L1和IRGM都在宿主-微生物应答中具有重要作用;包括微生物产物的感测、抗微生物肽的产生和细菌的细胞内杀伤。在亲本R 01中，特定目的3和4阐明了IBD新型小鼠模型（磷脂酰肌醇-3-激酶（PI 3 K）p1104亚基基因工程小鼠突变体）中自发性结肠炎的分子发病机制。在母基金中完成的实验表明，来自PI 3 K p110 D910 A/D910 A突变小鼠的巨噬细胞对toll样受体信号传导具有高反应性，并且在抗炎介质如IL-10存在下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的实验所描述的IL-12/23，Th 1和Th 17细胞因子介导的慢性肠道炎症，但最近的结果也表明，来自PI 3 K p110 D910 A/D910 A突变小鼠的巨噬细胞对肠道细菌的杀菌活性减弱。 这一出乎意料的结果1）表明这种小鼠模型可能为理解人类CD的发病机制提供了重要的试剂，2）导致了一个全新的研究领域，而这并不是最初科学提案的目标。因此，我们为实验室确定了一个与裁谈会直接相关的新的、重要的科学方向。我们建议在分子水平上表征PI 3 K 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。 公共卫生相关性：这种补充剂将加速对影响超过1，000，000美国公民的人类IBD发病机制的科学发现。这一补充预计将通过以下方式刺激经济：增加目前兼职工作人员的工作时间。否则，本项目的唯一支持位置将被终止。这也将支持与国家无菌啮齿动物资源中心合作的无菌小鼠实验。

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.