Influence of Dietary Botanical Supplements on Biological and Behavioral Resilience

摘要 在U19申请中提出的题为“膳食植物补充剂对健康的影响”的研究， 生物和行为弹性”代表了一个综合和跨学科的有凝聚力的计划， 全面解决RFA-OD-19-001目标和目的的研究方法。在 特别是，这个植物膳食补充剂研究中心（BDSRC）的主要目标是提供 通过临床前和临床研究线提供有价值的见解，可能为未来的临床试验提供信息 旨在确定膳食多酚补充剂是否可以提供对压力诱导的恢复力， 心理障碍我们已经通过严格的可行性研究表明， 补充BDPP可以提高对抑郁样行为的恢复力。我们有 鉴定出与免疫功能和神经元活性相关的生物分子系统， BDPP的生物可利用代谢物影响促进对压力的恢复力。我们注意到， 代谢物抑制外周白细胞衍生的炎性细胞因子，特别是IL-6的产生， 这一点很重要，因为研究发现IL-6的产生是一种关键的反应， 对压力的敏感性BDPP的代谢产物是否抑制下游病理生理学 应激诱导的IL-6直接影响神经元功能和行为的作用尚未确定。 因此，本BDSRC的项目1将表征我们的植物补充剂是否能抵抗 由应激引起的与IL-6活性增加相关的生理途径， 对抑郁样行为的易感性。项目1还将确定小胶质细胞中的生物靶点， 中间神经元和血脑屏障细胞受BDPP代谢产物的影响，通过最先进的细胞特异性 RNA测序和成像技术。项目2将直接与项目1协同作用，首先提供一个 评估BDPP的临床特性，以及它们是否与啮齿动物中观察到的相似。我们将 进行药代动力学和稳态特征分析，以确定人血浆中发现的生物可利用代谢物， 并证实存在对IL-6产生发挥生物学作用的代谢物。项目2将 还利用多变量自适应回归样条模型来鉴定特定代谢物或其组合， 负责调节IL-6表达的BDPP代谢物。此外，项目2将验证血浆IL-6 作为响应于BDPP处理的生物复原力的标志物，通过测试BDPP是否促进复原力， 针对响应于人类中的特里尔社会应激测试的血浆IL-6的上调。拟议 项目的设计和优化是为了相互协同，并与两者无缝集成 科学核心。总之，该提案提供了关于作用机制和 BDPP及其代谢物的临床特性，填补了现有数据中最关键的空白 优化设计未来的临床试验，以测试BDPP对压力的弹性。

Summary Abstract The studies proposed in this U19 application titled “The Influence of Dietary Botanical Supplements on Biological and Behavioral Resilience” represent a cohesive program of integrated and interdisciplinary research approaches that comprehensively address the objectives and purpose of RFA-OD-19-001. In particular, the principal objective of this botanical dietary supplement research center (BDSRC) is to provide valuable insight, through both pre-clinical and clinical lines of investigation that may inform a future clinical trial designed to determine if dietary polyphenol supplements can provide resilience against stress-induced psychological impairment. We have shown through rigorous feasibility studies utilizing stress-induced models of depression that supplementation with BDPP promotes resilience to depression-like behaviors. We have identified biomolecular systems associated with immune function and neuronal activity that specific bioavailable metabolites of BDPP influence to promote resilience to stress. We note that bioavailable metabolites suppressed production of peripheral leukocytes derived inflammatory cytokines, in particular IL-6, which is important to consider given studies that find production of IL-6 is a critical response that confers susceptibility to stress. Whether or not metabolites of BDPP suppress the downstream pathophysiological effects of stress-induced IL-6 that directly affect neuron function and behavior has yet to be established. Therefore, Project 1 of this BDSRC will characterize if our botanical supplement provides resilience against physiological pathways elicited by stress that are associated with increased IL-6 activity and that confer susceptibility to the onset of depressive-like behavior. Project 1 will also identify biological targets in microglia, interneurons, and blood brain barrier cells influenced by BDPP metabolites by state-of-the-art cell-specific RNA-sequencing and imaging techniques. Project 2 will directly synergize with Project 1 by first providing an assessment of the clinical properties of BDPP, and whether they parallel those observed in rodents. We will conduct a pharmacokinetic and steady-state profile to define bioavailable metabolites found in human plasma, and to confirm the presence of metabolites that exert biological effects against IL-6 production. Project 2 will also utilize a multivariate adaptive regression splines model to identify specific metabolites or combinations of BDPP metabolites responsible for modulating IL-6 expression. In addition, Project 2 will validate plasma IL-6 as a marker of biological resilience in response to BDPP treatment by testing if BDPP promotes resilience against upregulation of plasma IL-6 in response to the Trier Social Stress Test in humans. The proposed Projects are designed and optimized to synergize with each other, and to integrate seamlessly with the two Scientific Cores. Together, this proposal offers to provide critical information of the mechanism of action and the clinical properties of BDPP and its metabolites that fill the most critical gaps in the existing body of data needed to optimally design a future clinical trial to test resilient properties of BDPP in response to stress.