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

• 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
• 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

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.

在 通过触发多种机制来调节宿主免疫反应来感染。反过来 宿主诱导平衡的免疫响应，该免疫响应介导了蠕虫杀死的同时限制组织 损害。在此多PI探索性建议中，我们将内源性大麻素（ECB）系统确定为 以前无法识别的对这种动态宿主 - 螺旋相互作用的贡献者。脂质 信号分子ECB是人体的天然大麻样分子，可调节中性 诸如成瘾和喂养之类的行为。 ECB的受体在整个过程中表达 身体，包括免疫细胞，其中欧洲央行介导的信号传导会抑制炎症。 遵循巴西龙骨（NB）感染作为鼠标的小鼠模型 感染，我们观察到在感染 在功能上影响宿主免疫响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产生ECB，并确定推定的基因 用于NB和寄生线虫基因组中的欧洲元合成和降解酶 感染人类。我们的中心假设是ECB介导了双向交流 在决定宿主生理，免疫反应和蠕虫的宿主和蠕虫之间 寄生。 在AIM 1中，我们将研究蠕虫感染引起的内源性大麻素如何影响 NB感染后（i）量化欧洲央行水平和欧洲央行信号传导的托管； （ii）废除欧洲央行 药物学试剂或ECBR缺乏小鼠的接收器信号传导； （iii）整合 数据集以识别与统计模型的功能相互作用。在AIM 2中，我们将使用分子 工具和高吞吐量显微镜以描绘寄生虫中的内源性大麻素途径 蠕虫。我们将（i）使用药理学工具评估NB衍生的ECB和ECB信号传导 促进或废除NB中的欧洲央行信号传导； （ii）检查ECB在NB-HOST中的作用 使用新型共培养系统的免疫细胞相互作用。