Endocannabinoid regulation of host-helminth interaction

内源性大麻素对宿主与蠕虫相互作用的调节

基本信息

批准号：
9797211
负责人：
Nicholas Vincent DiPatrizio
金额：
$ 8.11万
依托单位：
UNIVERSITY OF CALIFORNIA RIVERSIDE
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-05-01 至 2021-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9797211
关键词：
2-arachidonylglycerol Affect Agonist Behavior Biological Assay Biology Brain CNR1 gene CNR2 gene Cannabis Cell Communication Cells Chronic Coculture Techniques Communication Complex Data Data Set Development Endocannabinoids Enzymes Evolution Exhibits Feeding behaviors Genes Genome Growth Helminths Human Immune Immune Evasion Immune response Immunity Immunology Impairment In Vitro Individual Infection Inflammation Intestines Life Life Cycle Stages Light Linear Models Lipids Measures Mediating Mediation Metabolic Pathway Metabolism Microscopy Molecular Morbidity - disease rate Mus Nematoda Nippostrongylus Nutrient Depletion Operating System Outcome Parasites Parasitic nematode Pathologic Pathway interactions Pharmacology Physiological Processes Physiology Principal Component Analysis Production Reagent Receptor Signaling Regulation Research Personnel Role Signal Pathway Signal Transduction Signaling Molecule Statistical Models System Testing Tissues addiction anandamide base cannabinoid receptor cannabinoid receptor antagonist defense response egg endocannabinoid signaling endogenous cannabinoid system feeding fitness gut-brain axis helminth infection immunoregulation inhibitor/antagonist insight mouse model neurotransmission new therapeutic target novel parasitism public health relevance receptor receptor expression relating to nervous system tool

项目摘要

Parasitic helminths exhibit the remarkable ability to establish chronic, often lifelong, infections by triggering multiple mechanisms to regulate the host immune response. In turn, the host induces a balanced immune response that mediates helminth killing while limiting tissue damage. In this multi-PI exploratory proposal, we identify the endocannabinoid (eCB) system as a previously unrecognized contributor to this dynamic host-helminth interaction. The lipid signaling molecules eCBs are the body’s natural cannabis-like molecules that regulate neural behaviors such as addiction and feeding. Receptors for eCBs are expressed throughout the body, including by immune cells, where eCB-mediated signaling can dampen inflammation. Following Nippostrongylus brasiliensis (Nb) infection as a mouse model of geohelminth infection, we observed significant eCB production and eCB receptor expression in the infected tissue that functionally impacted the host immune response and helminth egg burden. Moreover, we show that Nb produces eCBs at every life cycle stage, and identify putative genes for eCB synthetic and degradative enzymes in genome of Nb and parasitic nematodes that infect humans. Our central hypothesis is that eCBs mediate bi-directional communication between the host and helminth that dictates host physiology, immune response and helminth parasitism. In Aim 1 we will investigate how helminth infection-induced endocannabinoids affect the host by (i) quantifying eCB levels and eCB signaling following Nb infection; (ii) abrogating eCB receptor signaling by pharmacologic reagents or eCBR deficient mice; (iii) integrating the datasets to identify functional interactions with statistical models. In Aim 2 we will use molecular tools and high throughput microscopy to delineate the endocannabinoid pathway in the parasitic helminth. We will (i) evaluate Nb-derived eCBs and eCB signaling utilizing pharmacologic tools to promote or abrogate eCB signaling in Nb; and (ii) examine the role of eCBs in Nb-host immune cell interaction utilizing a novel co-culture system.

寄生蠕虫表现出显着的能力，可以造成慢性的、通常是终生的、通过触发多种机制来调节宿主免疫反应来引起感染。宿主诱导平衡的免疫反应，介导杀灭蠕虫，同时限制组织在这个多 PI 探索性提案中，我们将内源性大麻素 (eCB) 系统确定为以前未被认识到的这种动态宿主与蠕虫相互作用的贡献者。信号分子 eCB 是人体天然的类似大麻的分子，可调节神经 eCB 的受体在整个过程中都有表达，例如成瘾和进食。身体，包括免疫细胞，其中 eCB 介导的信号传导可以抑制炎症。巴西尼波圆线虫 (Nb) 感染后作为土蠕虫小鼠模型感染后，我们观察到感染者体内有显着的 eCB 产生和 eCB 受体表达在功能上影响宿主免疫反应和蠕虫卵负担的组织。此外，我们表明 Nb 在每个生命周期阶段都会产生 eCB，并识别出假定的基因用于 Nb 和寄生线虫基因组中的 eCB 合成和降解酶我们的中心假设是 eCB 介导双向通信。宿主和蠕虫之间的关系，决定宿主生理、免疫反应和蠕虫寄生。在目标 1 中，我们将研究蠕虫感染引起的内源性大麻素如何影响通过 (i) 量化 Nb 感染后的 eCB 水平和 eCB 信号传导来控制宿主；(ii) 消除 eCB；药理试剂或 eCBR 缺陷小鼠的受体信号转导；(iii) 整合在目标 2 中，我们将使用分子数据集来识别与统计模型的功能相互作用。工具和高通量显微镜来描绘寄生虫中的内源性大麻素途径我们将 (i) 利用药理学工具评估 Nb 衍生的 eCB 和 eCB 信号传导。促进或消除 Nb 中的 eCB 信号传导；以及 (ii) 检查 eCB 在 Nb 宿主中的作用利用新型共培养系统进行免疫细胞相互作用。