Influence of Dietary Botanical Supplements on Biological and Behavioral Resilience

膳食植物补充剂对生物和行为弹性的影响

• 批准号: 10447072
• 负责人: James Warren Murrough
• 金额: $ 119.28万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10447072
• 关键词: Acids; Address; Affect; Animal Model; Anti-Inflammatory Agents; Anxiety; Behavior; Behavioral; Biological; Biological Availability; Biological Markers; Biological Models; Biometry; Blood - brain barrier anatomy; Botanical dietary supplements; Botanicals; Brain; Cells; Chronic stress; Clinical; Clinical Pharmacology; Clinical Trials; Clinical Trials Design; Clinical assessments; Cognitive; Complement; Data; Dietary Polyphenol; Dissection; Drug Kinetics; Endothelial Cells; Event; Feasibility Studies; Functional disorder; Future; Grant; Human; Imaging Techniques; Immune; Immune response; Immunosuppression; Impairment; Inflammatory; Infrastructure; Interdisciplinary Study; Interleukin-6; Interneuron function; Interneurons; Investigation; Leukocytes; Maintenance; Mental Depression; Mental Health; Microglia; Modeling; Mus; Neurons; Nucleus Accumbens; Pathogenesis; Pathway interactions; Peripheral; Phenotype; Physiological; Plasma; Predisposition; Preparation; Production; Property; Protocols documentation; Psychological Stress; Regulation; Research; Research Design; Research Project Grants; Resources; Risk; Rodent; Role; Stress; Stress Tests; Supplementation; Synapses; Synaptic plasticity; System; Testing; Tissue Sample; Tissues; Trier Social Stress Test; Tumor-infiltrating immune cells; Up-Regulation; Validation; biological adaptation to stress; blood-brain barrier permeabilization; clinical development; clinical investigation; cohesion; cytokine; data management; depression model; depressive symptoms; design; dietary; human tissue; immune function; in vivo; insight; neuropsychiatric disorder; polyphenol; pre-clinical; preclinical study; prevent; programs; psychologic; quality assurance; resilience; response; stress related disorder; stressor; transcriptome sequencing

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.

摘要摘要 在本次U19应用中提出的研究标题为“饮食植物补充剂对 生物学和行为弹性”代表了综合和跨学科的凝聚力计划 全面解决RFA-OD-19-001的对象和目的的研究方法。在 特别是，这个植物饮食补充研究中心（BDSRC）的主要目标是提供 通过临床前和临床调查线可能会为未来的临床试验提供可有价值的见解 旨在确定饮食多酚补充剂是否可以为压力引起的弹性提供弹性 心理障碍。我们通过使用压力引起的模型的严格可行性研究表明 补充BDPP的抑郁症会促进对抑郁症样行为的韧性。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的可生物利用代谢产生的代谢产生了促进压力的弹性。我们注意到生物利用 代谢物抑制了衍生炎性细胞因子的外周白细胞的产生，特别是IL-6， 考虑到发现IL-6产生的研究是一个关键反应，这一点很重要 压力的敏感性。 BDPP的代谢物是否抑制下游的病理生理学 压力诱导的IL-6的影响直接影响神经元功能和行为尚未确定。 因此，如果我们的植物补充剂为反对的弹性，该BDSRC的项目1将表征 与IL-6活性增加和会议有关的压力引起的物理途径 对抑郁样行为发作的敏感性。项目1还将确定小胶质细胞的生物学靶标， 中间神经元和受BDPP代谢产生的血液屏障细胞受到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 评估BDPP的临床特性，以及它们是否平行于啮齿动物中观察到的临床特性。我们将 进行药代动力学和稳态特征，以定义在人血浆中发现的可生物利用代谢物， 并确认存在对IL-6产生发挥生物作用的代谢产物。项目2将 还利用多元自适应回归花纹模型来识别特定的代谢物或组合 BDPP代谢物负责调节IL-6表达。此外，项目2将验证血浆IL-6 通过测试BDPP是否促进弹性，作为生物弹性的标志 反对血浆IL-6的上调，以应对人类的Trier社会压力测试。提议 项目的设计和优化以相互协同，并与两者无缝集成 科学核心。该提案共同提供了有关行动机理和 BDPP及其代谢产物的临床特性填补了所需的现有数据体系中最关键的差距 最佳设计未来的临床试验，以测试BDPP的弹性特性，以应对压力。