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

项目概要/摘要 尽管联合抗逆转录病毒疗法（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）的人患有抑郁症。 虽然越来越多的证据表明，持续的全身性和中枢神经系统炎症是常见的 在重度抑郁症和艾滋病病毒感染者中观察到， 对艾滋病毒携带者和艾滋病毒携带者的调查仍然很差。在这个K01提案中，候选人假设有一个 肠道细菌和真菌群落之间的相互作用，如果被破坏，可能导致持续的 炎症和抑郁样表型在EcoHIV小鼠模型。候选人还假设 茯苓多糖是1，3-D-β-葡聚糖的天然产物，可以拯救EcoHIV诱导的抑郁样 行为，肠道细菌-真菌生态失调和持续炎症，基于初步结果 表明茯苓多糖具有抗抑郁作用，其依赖于抑制Dectin-1，一种模式- 识别β-D-葡聚糖受体。为了验证这一假设，提出了三个具体目标：（1）识别和 表型表征HIV诱导的抑郁样行为在EcoHIV小鼠模型中的性质。 (2)确定和研究HIV诱导的肠道微生物群改变以及炎症信号， 肠道循环和中枢神经系统(3)为了确定茯苓多糖治疗 改善HIV诱导的抑郁样行为，调节肠道微生物群和炎症信号 通过dectin-1抑制。为了实现这3个具体目标，需要4个短期培训步骤/目标： 精通HIV小鼠模型的社会行为表型和免疫特征的研究-- 候选人将由Atsushi Kamiya博士、Barbara Slusher博士和阿曼达布朗博士指导， 与大卫沃尔斯基和诺曼豪伊博士的咨询/合作。培训将在约翰 霍普金斯。(ii)为了成功进行16S和ITS2靶向宏基因组测序分析， 准确的生物统计学分析，正确解释和综合肠道微生物群的生物学意义 数据集--候选人将由约翰霍普金斯大学的罗伯特·约尔肯博士和莎拉·惠兰博士进行培训。(iii)到 接受基础科学实践培训以及天然产品药理学的教学培训 和药物研发的专家(iv)接受流行病学、临床 抑郁症的临床表现、生物标志物的选择、转化疗法和研究方法 贾斯汀·麦克阿瑟博士的艾滋病毒。最重要的是，K01提案的长期目标是开发一种 独立的研究实验室，配备独立研究天然产品的治疗效果， HIV相关神经精神疾病中肠道细菌-真菌生态失调诱导的炎症机制， 并通过成功地争取资金来发展一条有计划的研究路线。

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.