Influence of Dietary Botanical Supplements on Biological and Behavioral Resilience

摘要摘要 在这份U19申请中提出的题为“膳食植物性补充剂对 生物和行为复原力“代表了一项综合和跨学科的凝聚力计划 全面解决RFA-OD-19-001目标和目的的研究方法。在……里面 具体地说，这个植物性膳食补充剂研究中心(BDSRC)的主要目标是提供 有价值的洞察力，通过临床前和临床研究路线，可能为未来的临床试验提供参考 旨在确定膳食多酚补充剂是否可以提供对压力诱导的弹性 心理障碍。我们已经通过使用压力诱导模型的严格的可行性研究表明 补充BDPP可提高对抑郁症样行为的复原力。我们有 已识别的与免疫功能和神经元活动相关的生物分子系统 BDPP的生物可利用代谢产物对提高抗逆性有影响。我们注意到生物利用度 代谢产物抑制外周血白细胞衍生的炎性细胞因子的产生，特别是IL-6， 有研究发现，IL-6的产生是一种关键的反应，这一点值得考虑 对压力的敏感性。BDPP代谢产物是否抑制下游病理生理 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，该BDSRC的项目1将表征我们的植物补充剂是否提供了对 应激诱导的与IL-6活性增加相关的生理通路 容易出现类似抑郁的行为。项目1还将确定小胶质细胞中的生物靶点， 细胞特异性BDPP代谢产物对中间神经元和血脑屏障细胞的影响 RNA测序和成像技术。项目2将直接与项目1协同，方法是首先提供 评估BDPP的临床特征，以及它们是否与在啮齿类动物中观察到的相似。我们会 进行药代动力学和稳态曲线以确定在人体血浆中发现的生物可用代谢物， 并确认是否存在对IL-6产生产生生物影响的代谢物。项目2将 还利用多变量自适应回归样条法模型来识别特定的代谢物或 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 通过测试BDPP是否促进弹性来作为响应BDPP治疗的生物弹性的标志 对抗人类Trier社会应激测试中血浆IL-6的上调。建议数 项目的设计和优化旨在相互协同，并与两者无缝集成 科学核心。综上所述，这项提案提供了有关行动机制和 BDPP及其代谢物的临床特性fi是现有数据中最关键的空白 优化设计一项未来的临床试验，以测试BDPP在应对压力时的弹性特性。

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.