Role of DC Wnt/beta-catenin signaling in Toxoplasma infection

DC Wnt/β-连环蛋白信号在弓形虫感染中的作用

• 批准号: 8619823
• 负责人: ERIC Y DENKERS
• 金额: $ 23.25万
• 依托单位: CORNELL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-12-01 至 2015-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8619823
• 关键词: Affect; Antigens; Attenuated; Bone Marrow; Cells; Cellular Immunity; Chemicals; Communicable Diseases; Cyst; Cytokine Signaling; Data; Dendritic Cells; Development; Disabled Persons; Disease; Dose; Equilibrium; Foundations; Generations; Genes; Human; ITGAX gene; Immune; Immune Tolerance; Immune response; Immune system; Immunity; Immunocompromised Host; Immunotherapy; Inbred Mouse; Infection; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Inflammatory Response; Interferons; Interleukin-10; Interleukin-12; Intestinal Mucosa; Intestines; Life; Ligands; Malignant Neoplasms; Mediating; Modeling; Mouse Strains; Mus; Opportunistic Infections; Oral; Parasites; Pathology; Pathway interactions; Phenotype; Physiologic pulse; Play; Population; Predisposition; Production; Public Health; Regulation; Research; Resistance; Role; Signal Pathway; Signal Transduction; Source; Staging; Systemic infection; T cell response; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Time; Toxoplasma; Toxoplasma gondii; Toxoplasmosis; Transgenic Mice; Transgenic Organisms; Vaccinated; beta catenin; biodefense; congenital infection; cytokine; design; immune activation; immunopathology; improved; in vivo; microbial; mouse model; novel; pathogen; programs; public health relevance; response

Project Summary/Abstract The long-term objective of this proposal is to understand how tolerance versus immunity is regulated during microbial infection. The research proposed uses mouse infection with the protozoan parasite Toxoplasma gondii, a Th1-inducing pathogen, to probe regulation of immunity locally and during disseminated infection. Intracellular signaling along a Wnt/¿-catenin pathway is emerging as an important regulatory axis in the immune system. Activation of this pathway in dendritic cells promotes tolerance in the intestinal mucosa. Using transgenic mice possessing dendritic cell-specific ¿-catenin deletion and mice in which dendritic cell ¿-catenin is constitutively active, we will determine how dendritic cell ¿-catenin signaling impacts inflammation and immunity during Toxoplasma infection. The central hypothesis of the proposal is that Wnt/¿-catenin signaling promotes a tolerogenic phenotype in DC that limits immune-mediated damage Toxoplasma infection, but that also places limits on the ability to generate protective T cell-mediated immunity. The hypothesis will be tested using two specific aims. Aim 1: Determine the function of dendritic cell Wnt/¿-catenin in intrinsic cytokine and signaling responses and in ability to stimulate antigen specific T cell responses. We will establish how Wnt/¿-catenin signaling impacts other immunity-related signaling pathways in dendritic cells, and in turn how this affects T subset differentiation. Aim 2: Understand how DC Wnt/¿-catenin signaling impacts inflammation and immunity during in vivo infection. We will determine the impact of Wnt/¿-catenin signaling on Toxoplasma-induced inflammation in the intestinal mucosa, and we will determine how the role of this pathway in emergence of T cell immunity during in vivo infection. The importance of the research is that the data generated by following these specific aims will deepen our understanding of regulation of immunity and inflammation during infection, in particular as related to Wnt/¿- catenin signaling which is poorly understood at present. The ultimate impact of the research is that it can be expected to ultimately identify novel targets for immunotherapy in inflammatory disease, as well as providing new targets to promote immunity during infectious disease.

项目总结/摘要 本提案的长期目标是了解耐受性与免疫性是如何调节的 在微生物感染期间。这项研究利用小鼠感染原生动物寄生虫 弓形虫，一种Th 1诱导病原体，探索局部和期间的免疫调节 播散性感染细胞内信号沿着Wnt/-连环蛋白通路正在成为一个重要的 免疫系统中的调节轴。树突状细胞中这一通路的激活促进了免疫耐受。 肠粘膜使用具有树突状细胞特异性连环蛋白缺失的转基因小鼠和 哪种树突状细胞连环蛋白是组成性活性的，我们将确定树突状细胞连环蛋白信号传导 在弓形虫感染期间影响炎症和免疫。该提案的核心假设是 Wnt/β-catenin信号促进DC中的耐受性表型，限制免疫介导的损伤， 弓形虫感染，但这也限制了产生保护性T细胞介导的能力。 免疫力该假设将使用两个具体目标进行检验。目的1：确定树突状细胞的功能 细胞Wnt/<$-连环蛋白在内在细胞因子和信号传导反应中的作用以及刺激抗原特异性T细胞的能力 细胞反应。我们将确定Wnt/β-catenin信号传导如何影响其他免疫相关信号传导 树突状细胞中的信号通路，以及这反过来如何影响T亚群分化。目标2：了解DC如何 Wnt/β-连环蛋白信号传导影响体内感染期间的炎症和免疫。康贝特人将以 Wnt/<$-catenin信号对弓形虫诱导的肠粘膜炎症的影响，我们 将确定该途径在体内感染期间T细胞免疫出现中的作用。的 研究的重要性在于，通过遵循这些特定目标产生的数据将加深我们的 了解感染期间免疫和炎症的调节，特别是与Wnt/？ 目前尚不清楚的连环蛋白信号传导。这项研究的最终影响是， 有望最终确定炎症性疾病免疫治疗的新靶点，以及 提供了新的靶点，以促进传染病期间的免疫力。