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

基本信息

批准号：
10287962
负责人：
James Warren Murrough
金额：
$ 42.38万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
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/10287962
关键词：
Acids Address Affect Animal Model Anti-Inflammatory Agents Anxiety Behavior Behavioral Bioavailable 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

项目摘要

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.

摘要摘要这份 U19 申请中提出的研究题为“膳食植物补充剂对健康的影响” 生物和行为弹性”代表了综合和跨学科的有凝聚力的计划全面解决 RFA-OD-19-001 的目标和目的的研究方法。特别是，该植物膳食补充剂研究中心（BDSRC）的目标原则是提供通过临床前和临床研究线提供宝贵的见解，可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抵抗压力引起的恢复能力我们利用压力诱发模型通过严格的可行性研究证明了这一点。补充 BDPP 可以增强对抑郁样行为的恢复能力。确定了与免疫功能和神经活动相关的生物分子系统 BDPP 的生物可利用代谢物可影响促进应激恢复能力。代谢物抑制外周白细胞衍生的炎症细胞因子的产生，特别是 IL-6，鉴于研究发现 IL-6 的产生是一种关键反应，因此考虑这一点很重要 BDPP 的代谢物是否抑制下游病理生理学。应激诱导的 IL-6 直接影响神经功能和行为的作用尚未确定。因此，本 BDSRC 的项目 1 将描述我们的植物补充剂是否能提供抵抗力应激引起的生理途径与 IL-6 活性增加相关，并赋予项目 1 还将确定小胶质细胞中的生物靶点，受最先进的细胞特异性 BDPP 代谢物影响的中间神经元和血脑屏障细胞 RNA 测序和成像技术将首先提供一个与项目 1 直接协同的技术。评估 BDPP 的临床特性，以及它们是否与在啮齿动物中观察到的相似。进行药代动力学和稳态分析以确定人血浆中发现的生物可利用的代谢物，并确认对 IL-6 产生产生生物效应的代谢物的存在，项目 2 将进行。还利用多元自适应回归样条模型来识别特定代谢物或代谢物组合此外，项目 2 将验证血浆 IL-6 的 BDPP 代谢物。通过测试 BDPP 是否促进恢复力，作为对 BDPP 治疗的生物恢复力标志对抗人类特里尔社会压力测试中血浆 IL-6 的上调。项目经过设计和优化，可以相互协同，并与两者无缝集成科学核心。该提案提供了作用机制和作用机制的关键信息。 BDPP 及其代谢物的临床特性填补了现有所需数据中最关键的空白优化设计未来的临床试验，以测试 BDPP 应对压力的弹性特性。