Dscam function in innate immunity

Dscam 在先天免疫中的作用

基本信息

批准号：
8462530
负责人：
George Dimopoulos
金额：
$ 30.52万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-06-01 至 2015-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8462530
关键词：
Address Adhesives Affinity Alternative Splicing Anopheles Genus Anopheles gambiae Anti-Bacterial Agents Bacteria Biological Assay Cell Line Characteristics Complex Culicidae Development Down Syndrome Cell Adhesion Molecule Exons Exposure to Generations Genes Genomics Goals Immune Immune response Immune system Immunologic Surveillance Individual Infection Insecta Malaria Maps Microbe Modeling Molecular Natural Immunity Parasites Pathway interactions Pattern Pattern recognition receptor Plasmodium Play Production Property Protein Region RNA Interference RNA Splicing Regulation Research Research Proposals Resistance Role Signal Pathway Specificity Staining method Stains Study models Testing Transgenic Organisms Virus antimicrobial base combat coping fight against functional genomics fungus in vivo insight killings microbial pathogen public health relevance receptor research study tool

项目摘要

DESCRIPTION (provided by applicant): Anopheles gambiae and other insects utilize a variety of strategies to combat microbial invaders. The long-term goal of the PIs research is to characterize and understand the mechanisms of innate immunity used by the mosquito against microbes. This proposal focuses on the particular role of the Down syndrome cell adhesion molecule (Dscam) as a hypervariable immune surveillance receptor. Dscam's complex genomic organization and remarkable properties suggest that it plays multiple roles in immune defense: In A. gambiae, alternative splicing of the AgDscam gene produces >31,920 alternative splice- form receptors with different adhesive characteristics and specificities. AgDscam produces microbe-specific splice-form repertoires upon immune challenge and is involved in both antibacterial and anti-Plasmodium defense. The studies outlined here will further test the hypothesis that, as previously shown for challenge with a limited number of bacteria, this phenotypic plasticity of the AgDscam gene allows it to produce receptor molecules with potent antimicrobial activity and high affinity for bacteria and the Plasmodium parasite. To test this hypothesis, the proposed studies will use RNAi silencing, immunohistochemical staining, microarray analyses, and interaction analyses to determine (in Specific Aim 1) the regulation of AgDscam splicing and production of splice form repertoire by microbe challenge and the innate immune pathways, and (in Aims 2) the specific splice-form repertoires involved in these defenses and interactions with microbes. We will finally test the anti-Plasmodium defense specificity and efficacy of AgDscam in genetically modified mosquito lines that over-express pathogen specific splice forms (in Specific Aim 3). These analyses will elucidate one of the most remarkable players of the insect innate immune system, which allows it to cope with a broad spectrum of microbes through the microbe challenge specific production of pattern recognition receptors. The study will also assess the feasibility to use AgDscam for the generation of Plasmodium resistant mosquitoes that could be used for the development of a malaria control strategy.

描述（由申请人提供）：冈比亚和其他昆虫采用各种策略来对抗微生物入侵者。 PIS研究的长期目标是表征和了解蚊子对微生物使用的先天免疫的机制。该提案的重点是唐氏综合征细胞粘附分子（DSCAM）作为高变量的免疫监测受体的特殊作用。 DSCAM复杂的基因组组织和显着特性表明，它在免疫防御中起多种作用：在冈比亚杂志中，AgDSCAM基因的替代剪接产生> 31,920个具有不同粘合性特征和特异性的替代剪接形式的受体。 AgDSCAM在免疫挑战时会产生微生物特异性的剪接形式，并参与抗菌和抗质量防御。此处概述的研究将进一步检验以下假设：如前所述的细菌数量有限的挑战所示，AgDSCAM基因的表型可塑性使其能够产生具有有效的抗菌活性和对细菌的高亲和力的受体分子和寄生虫的高亲和力。为了检验这一假设，提出的研究将使用RNAi沉默，免疫组织化学染色，微阵列分析和相互作用分析，以确定（在特定目的1）调节AGDSCAM剪接和通过微生物挑战的剪接形式产生的剪接形式的产生，并通过微生物挑战和先天的免疫路径和（在目标范围内）进行了范围和（在目标范围内），并在特定的范围内进行了辩护2）。我们最终将测试AgDSCAM在过度表达病原体特异性剪接形式的转基因蚊中的抗质量防御特异性和疗效（在特定的目标3中）。这些分析将阐明昆虫先天免疫系统中最引人注目的参与者之一，这使其可以通过微生物挑战模式识别受体的特定生产来应对广泛的微生物。该研究还将评估使用AgDSCAM用于产生抗疟原虫蚊子的可行性，这些蚊子可用于开发疟疾控制策略。