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

项目摘要/摘要 尽管联合抗逆转录病毒疗法(CART)得到了普遍应用和成功，但超过30%的人 患有人类免疫缺陷病毒感染(PLWHIV)的美国人患有抑郁症。 尽管越来越多的证据表明，持续性的全身和中枢神经系统炎症通常是 观察重度抑郁障碍和PLWHIV患者抑郁的病理生理机制 在PLWHIV中，对艾滋病毒的调查仍然很少。在这份K01提案中，候选人假设有一个 肠道细菌和真菌群落之间的串扰，如果被破坏，可能导致持续的 EcoHIV小鼠模型中的炎症和抑郁样表型。候选人还假设 1，3-D-β-葡聚糖的天然产物Pachyman可以拯救EcoHIV诱导的抑郁样疾病 基于初步结果的行为、肠道细菌-真菌失调和持续性炎症 结果表明，茯苓多糖具有抗抑郁作用，这种作用依赖于Dectin-1的抑制，这种模式- 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 在EcoHIV小鼠模型中，表型特征描述了HIV诱导的抑郁样行为的性质。 (2)识别和研究HIV诱导的肠道微生物区系的变化与炎症信号在 肠道、循环和中枢神经系统。(3)确定Pachyman治疗是否 改善HIV诱导的抑郁样行为，调节肠道微生物区系和炎症信号 通过抑制Dectin-1的表达。为实现3个具体目标，需要4个短期培训步骤/目标：(I) 熟练研究HIV小鼠模型的社会行为表型和免疫特征-- 候选人将由神谷、芭芭拉·斯卢舍和阿曼达·布朗博士指导， 与大卫·沃尔斯基博士和诺曼·豪伊博士的咨询/合作。培训将在Johns进行 霍普金斯大学。(Ii)为了成功地进行16S和ITS2靶向元基因组测序图谱， 准确的生物静力学分析，并从肠道微生物区系中正确解释和合成生物学意义 数据集--候选人将在约翰·霍普金斯大学接受罗伯特·约尔肯博士和萨拉·惠兰博士的培训。(Iii) 接受基础科学实践培训和天然产物药理学教学培训 以及Slusher博士的药物开发。(4)接受流行病学、临床学的知识和技能培训 抑郁症的临床表现、生物标记物选择、转化疗法和研究方法 作者：贾斯汀·麦克阿瑟博士。最重要的是，这项K01提案的长期目标是开发一种 独立研究实验室，可独立研究天然产品对癌症的治疗效果 肠道细菌-真菌失调在HIV相关神经精神疾病中诱导的炎症机制， 并通过成功地竞争资金来开发一系列计划研究。

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.