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.

寄生蠕虫表现出建立慢性的，通常是终身的， 通过触发多种机制来调节宿主的免疫反应。符合要求的细粉则随 宿主诱导平衡的免疫反应，介导蠕虫杀灭，同时限制组织 损害在这个多PI探索性提议中，我们将内源性大麻素（eCB）系统确定为 一种以前未被认识到的导致这种动态宿主-蠕虫相互作用的因素。脂质 信号分子eCB是人体天然的大麻样分子， 成瘾和进食等行为。eCB的受体在整个细胞中表达， 身体，包括免疫细胞，eCB介导的信号传导可以抑制炎症。 巴西日本圆线虫（Nippostrongylus brasiliensis，Nb）感染后作为土源蠕虫的小鼠模型 感染，我们观察到显着的eCB生产和eCB受体的表达，在感染 功能上影响宿主免疫反应和蠕虫卵负荷的组织。 此外，我们发现Nb在每个生命周期阶段都产生eCB，并确定了推定的基因 对于Nb和寄生线虫基因组中的eCB合成和降解酶， 感染人类我们的中心假设是eCB介导双向通信 决定宿主生理、免疫反应和寄生虫 寄生 在目标1中，我们将研究蠕虫感染诱导的内源性大麻素如何影响 通过（i）在Nb感染后定量eCB水平和eCB信号传导;（ii）消除eCB 通过药理学试剂或eCBR缺陷小鼠的受体信号传导;（iii）整合 数据集来识别与统计模型的功能交互。在目标2中，我们将使用分子 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 寄生虫我们将（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。 免疫细胞相互作用，利用一种新的共培养系统。