Macrophage Gene Expression in Mucosal Inflammation

粘膜炎症中巨噬细胞基因的表达

• 批准号: 7833502
• 负责人: SCOTT E PLEVY
• 金额: $ 5.97万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-09-01 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7833502
• 关键词: Affect; Anti-Bacterial Agents; Anti-Inflammatory Agents; Anti-inflammatory; Area; Attenuated; Autophagocytosis; Bacteria; Bacterial Infections; Chronic; Colitis; Collaborations; Crohn' s disease; Defect; Development; Disease; Disease susceptibility; Enteral; Enterobacteriaceae; Epithelial Cells; Event; Funding; Gene Expression; Genetically Engineered Mouse; Germ-Free; Gnotobiotic; Hour; Human; Immune; Immune response; Infection; Inflammation Mediators; Inflammatory Bowel Diseases; Inflammatory Response; Inflammatory disease of the intestine; Interleukin-10; Intestines; Laboratories; Lymphoid Tissue; Mediating; Molecular; Mucositis; Mus; Mutant Strains Mice; NADPH Oxidase; Organism; Parents; Pathogenesis; Pathway interactions; Phagocytosis; Phagolysosome; Phagosomes; Phosphatidylinositols; Phosphotransferases; Positioning Attribute; Production; Reagent; Receptor Signaling; Recombinant DNA; Recovery; Recruitment Activity; Research; Resources; Rodent; Role; Susceptibility Gene; Talents; Technology; Time; Toll-like receptors; United States National Institutes of Health; Work; antimicrobial peptide; bactericide; base; cytokine; in vivo; killings; macrophage; microbial; microbial host; mouse model; mutant; novel; parent grant; pathogenic bacteria; public health relevance; research study; response

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.

描述（由申请人提供）：NOT-OD-09-058 NIH宣布为竞争性修订应用程序提供恢复CT资金。这是对母体R01、2 R01 DK054452的竞争补充应用，“粘膜炎症中的巨噬细胞基因表达”。它基于在父授予的主持下获得的丰富初步结果，该结果将该项目移至全新的方向。 最近描述的是人类克罗恩病（CD）中的易感基因（CD）强调了与肠子菌群的先天免疫相互作用是疾病发病机理中的关键事件。具体而言，CD敏感性基因Card15，Atg16L1和IRGM都在宿主微生物反应中起重要作用。包括感测微生物；产物，抗菌肽的产生以及细菌的细胞内杀死。在母体R01中，特异性目标3和4阐明了在磷脂酰inositol-3-激酶（PI3K）的p1104亚基中，在IBD的新型IBD，基因工程小鼠突变体的新型小鼠模型中，自发发生的结肠炎的分子发病机理。父母赠款中完成的实验表明，来自PI3K P110D910A/D910A突变小鼠的巨噬细胞对Toll样受体信号传导具有超反应性，并且在存在抗炎介质的情况下下调炎症反应的能力有缺陷，例如IL-10。尽管这些发现有助于解释由IL-12/23，Th1和Th17细胞因子介导的慢性肠道炎症，但最近的结果也表明，PI3K PI3K p110d910a/d910a突变体的巨噬细胞减弱了针对肠细菌的细菌性活性。 这个意外的结果1）表明，该小鼠模型可能会提供一种重要的试剂，以理解人CD的发病机理，而2）导致一个全新的研究领域，这不是原始科学建议的目标的一部分。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中的杀菌活性。为了实现这些目标，我们建立了新的合作，有必要向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：这种补充将加速有关影响100万美国公民的人类IBD发病机理的科学发现。预计这种补充剂将通过：实现当前兼职人员的小时数来刺激经济。否则，唯一支持在该项目上的位置将被终止。这还将与国家gnotobiotic啮齿动物资源中心一起支持无菌小鼠的实验。