Exploring a natural product to modulate aberrant gut bacterial-fungal interactions as pathological mechanisms underlying HIV-associated depression

探索一种天然产物来调节异常肠道细菌-真菌相互作用作为艾滋病毒相关抑郁症的病理机制

• 批准号: 10594053
• 负责人: Xiaolei Zhu
• 金额: $ 13.51万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-15 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10594053
• 关键词: 3-Dimensional; Animals; Attention; Bacteria; Basic Science; Behavior; Biological; Biological Assay; Blood; Brain region; Butyrates; Central Nervous System; Characteristics; Chinese Traditional Medicine; Circulation; Clinical; Clostridium; Cocos; Collaborations; Communities; Data; Data Set; Disease Progression; Epidemiology; Fatty Liver; Feces; Functional disorder; Funding; General Population; Genetic; Genetic Transcription; Goals; HIV; HIV Infections; High Pressure Liquid Chromatography; High Prevalence; Immune; Impairment; Infection; Inflammation; Inflammatory; Knowledge; Laboratory Research; Lactobacillus; Limulus; Major Depressive Disorder; Mediating; Medicinal Herbs; Mental Depression; Mentors; Mus; Myeloid Cells; Natural Products; Nature; Obese Mice; Pathologic; Pathway interactions; Patients; Pattern Recognition; Persons; Phagocytes; Pharmacology; Phenotype; Play; Poria; Prevention; Refractory; Research; Research Methodology; Rodent Model; Role; Signal Transduction; Social Behavior; Social Interaction; Sodium Dextran Sulfate; Step training; Sucrose; Testing; Time; Training; Virus Diseases; Virus Replication; Volatile Fatty Acids; antidepressant effect; antiretroviral therapy; behavior test; behavioral phenotyping; beta-Glucans; biomarker selection; comorbidity; dectin 1; depressive symptoms; drug development; dysbiosis; forced swim test; fungus; gut bacteria; gut inflammation; gut microbiota; inflammatory marker; metagenomic sequencing; microbial; mouse model; neuroinflammation; neuropsychiatric disorder; novel; polyglucosan; preclinical study; preference; product development; protective effect; psychiatric comorbidity; receptor; skills training; social; success; systemic inflammatory response; translational therapeutics; treatment effect

Project Summary/Abstract Despite the universal use and success of combination antiretroviral therapy (CART), more than 30% of people living with human immunodeficiency virus infection (PLWHIV) in the US are suffering from depression. Although accumulating evidence suggests that sustained systemic and CNS inflammation are commonly observed in patients with major depressive disorder and PLWHIV, the pathophysiology underlying depression among PLWHIV remain poorly investigated. In this K01 proposal, the candidate hypothesizes that there is a crosstalk between the gut bacterial and fungal communities, which if disrupted, may lead to sustained inflammation and depressive-like phenotypes in the EcoHIV mouse model. The candidate also hypothesizes that pachyman, a natural product of 1,3-D-β-glucan, can rescue the EcoHIV-induced depressive-like behaviors, gut bacterial-fungal dysbiosis, and sustained inflammation, based on the preliminary results showing that pachyman has an antidepressant effect which is dependent on inhibition of Dectin-1, a pattern- recognition β-D-Glucan receptor. To test the hypothesis, three specific aims are proposed: (1) To identify and phenotypically characterize the nature of HIV-induced depressive-like behaviors in the EcoHIV mouse model. (2) To identify and study HIV-induced alterations in gut microbiota in conjunction with inflammatory signaling in the gut, circulation and in the central nervous system. (3) To determine whether pachyman treatment ameliorates HIV-induced depressive-like behaviors, and modulates gut microbiota and inflammatory signaling via dectin-1 inhibition. To achieve the 3 specific aims, 4 short-time training steps/goals are required: (i) To become proficient at the study of social behavior phenotypes and immune characteristics of HIV mice models-- the candidate will be mentored by Drs. Atsushi Kamiya, Barbara Slusher, and Amanda Brown, with Consultancy/collaboration with Drs. David Volsky and Norman Haughey. Training will occur at Johns Hopkins. (ii) To successfully conduct 16S and ITS2 targeted Metagenomic sequencing profiling, perform accurate biostatics analyses, and correctly interpret and synthesize biological meaning from gut microbiota datasets--the candidate will be trained by Drs. Robert Yolken and Sarah Wheelan at Johns Hopkins. (iii) To receive basic science hands-on training as well as didactic training in the pharmacology of natural products and drug development by Dr. Slusher. (iv) To receive knowledge and skills training in epidemiology, clinical manifestations, biomarkers selection, translational therapeutics, and research methodology for depression in PLWHIV by Dr. Justin McArthur. Above all, the long-term goal of this K01 proposal is to develop an independent research laboratory equipped to independently study the treatment effects of natural products on gut bacterial-fungal dysbiosis-induced inflammatory mechanisms in HIV-associated neuropsychiatric disorders, and to develop a programmatic line of research by successfully competing for funding.

项目摘要/摘要 尽管联合使用抗逆转录病毒疗法（CART）的普遍使用和成功，但超过30％的人 在美国患有人类免疫缺陷病毒感染（PLWHIV）患有抑郁症。 尽管积累的证据表明持续的全身和中枢神经系统注射通常是 在重度抑郁症和PLWHIV患者中观察到的病理生理学抑郁症的病理生理学 在PLWHIV中，调查仍然很少。在此K01提案中，候选人假设有一个 肠道细菌与真菌群落之间的串扰，如果被破坏，可能会导致持续 生态小鼠模型中的炎症和抑郁样表型。候选人还假设 那个Pachyman是1,3-D-β-葡聚糖的天然产物，可以挽救生态诱导的抑郁样 基于初步结果 表明帕奇曼具有抗抑郁作用，取决于抑制dectin-1，一种模式 - 识别β-D-葡聚糖受体。为了检验假设，提出了三个具体目标：（1）识别和 表型从ECOHIV小鼠模型中表征了HIV诱导的抑郁样行为的性质。 （2）识别和研究HIV诱导的肠道微生物群的改变，并结合炎症信号传导 肠道，循环和中枢神经系统。 （3）确定Pachyman是否治疗 改善艾滋病毒引起的抑郁样行为，并调节肠道菌群和炎症信号传导 通过dectin-1抑制。为了实现3个特定目标，需要4个短期培训步骤/目标：（i） 精通艾滋病毒小鼠模型的社会行为表型和免疫特征的研究 - 候选人将由博士召集。 Atsushi Kamiya，Barbara Slusher和Amanda Brown与 与Drs的咨询/合作。大卫·沃尔斯基（David Volsky）和诺曼·霍希（Norman Haughey）。培训将在约翰斯进行 霍普金斯。 （ii）成功进行16S和ITS2靶向元基因组测序分析，执行 准确的生物统计学分析，并正确解释和合成肠道菌群的生物学意义 数据集 - 候选人将由DRS培训。约翰·霍普金斯（Johns Hopkins）的罗伯特·约尔肯（Robert Yolken）和莎拉·惠兰（Sarah Wheelan）。 （iii）至 接受基础科学动手培训以及天然产品药理学的教学培训 和Slusher博士的药物开发。 （iv）接受流行病学的知识和技能培训，临床 抑郁症的表现，生物标志物选择，转化疗法和研究方法论 贾斯汀·麦克阿瑟（Justin McArthur）博士的PLWHIV。最重要的是，该K01提案的长期目标是开发 独立的研究实验室，配备了独立研究天然产品对治疗的影响 肠道细菌 - 杂种营养不良诱导的艾滋病毒相关神经精神疾病中的炎症机制， 并通过成功竞争资金来开发计划的研究线。