Suppression of Immune Signatures of Stress by Polyphenols Supplements

多酚补充剂抑制压力的免疫特征

• 批准号: 10447073
• 负责人: Giulio Maria Pasinetti
• 金额: $ 39.73万
• 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/10447073
• 关键词: Behavioral; Biological; Botanical dietary supplements; Immunosuppression; Stress; polyphenol; resilience

Summary/Abstract The goal of Project 1 is to establish that a botanical supplement provides resilience against stress-induced pathophysiological responses that confer susceptibility to depressive behavior. This proposal will investigate how polyphenol metabolites of a bioactive dietary polyphenol preparation (BDPP) engage biomolecular and genetic targets in microglia, medium spiny neurons (MSNs), and blood brain barrier (BBB) cells to promote resilience of neuronal function and behavior in response to stress. Recent studies show that dysfunctional immune activity confers susceptibility to stress by affecting activity of these aforementioned cells. Systemic upregulation of inflammatory cytokines, in particular interleukin-6 (IL-6), by stress is observed in model systems of depression, as well as in patients with MDD. From preliminary studies involving a validated model of social stress, we show persistent IL-6 expression from leukocytes affects the BBB function only in stress- susceptible mice. We present evidence that BDPP bioavailable metabolites may promote resilience to social stress by suppressing production of cytokines, which is associated with maintenance of BBB integrity. Our first goal is therefore to establish if BDPP provides resilience against stress-induced depression by targeting mechanisms associated with BBB function. This aim will determine whether a botanical supplement prevents BBB permeability and infiltration of peripheral immune factors through the neuroendothelium, and will characterize biomolecular targets of BDPP metabolites in endothelial cells. Our preliminary studies show BDPP supplementation suppresses stress-induced microglia hyper-ramification and upregulation of inflammatory genes, which are associated with stress-susceptibility. Our second goal is to conduct an unbiased screen to identify molecular bioactivities of BDPP metabolites in microglia in response to stress. This aim involves a cell-specific RNA-sequencing technique termed translating ribosomal affinity purification (TRAP). Moreover, Aim 2 will characterize how increased activity of toll/nod-like receptors in microglia confer susceptibility to stress-induced depression, and act as proximate biological targets for BDPP metabolites. Finally, we show how BDPP metabolites prevent maladaptive glutamatergic synapse generation in the NAc in response to stress by regulating expression of synaptic genes in MSNs. We also show that peripheral IL-6 production by peripheral leukocytes in response to stress is critical for facilitating aberrant synapse formation in the NAc. The final goal will therefore be to conduct an unbiased screen to identify molecular bioactivities of BDPP metabolites in D2 MSNs using the TRAP method and to investigate if peripheral IL-6 diffusion into the brain activates microglia via the IL-6R to effect regulation of NAc synapse densities. This would provide a mechanism for why suppression of peripheral IL-6 by a botanical supplement can promote resilient behaviors for a future clinical trial. Together, Project 1 will validate that pathophysiological responses associated with IL-6 can be suppressed by a botanical supplement to promote resilience to stress.

摘要/摘要 项目1的目标是确定一种植物补充剂可以提供对压力诱导的弹性 导致抑郁行为易感性的病理生理反应。这项提案将调查 生物活性膳食多酚制剂(BDPP)的多酚代谢产物如何与生物分子和 小胶质细胞、中等刺神经元(MSN)和血脑屏障(BBB)细胞中的遗传靶点 神经功能和行为在应激反应中的弹性。最近的研究表明，功能障碍 免疫活动通过影响上述细胞的活动而增加对压力的敏感性。系统性 应激可上调炎性细胞因子，尤其是白介素6。 抑郁症系统，以及MDD患者。来自一个经过验证的模型的初步研究 在社会应激中，我们发现白细胞持续的IL-6表达只在应激时才会影响血脑屏障功能- 易受感染的小鼠。我们提出的证据表明，BDPP生物可利用的代谢物可能会提高对社会的适应能力 通过抑制细胞因子的产生而产生的压力，这与维持血脑屏障的完整性有关。我们的第一次 因此，目标是确定BDPP是否通过靶向提供对压力诱导的抑郁的弹性 与血脑屏障功能相关的机制。这一目标将决定一种植物补充剂是否可以预防 血脑屏障通透性和外周免疫因子通过神经内皮的渗透，并将 确定BDPP代谢产物在内皮细胞中的生物分子靶点。我们的初步研究表明 补BDPP抑制应激诱导的小胶质细胞过度分化和上调 炎症基因，这与应激敏感性有关。我们的第二个目标是进行一次 无偏筛选以确定小胶质细胞中BDPP代谢物在应激反应中的分子生物活性。 这一目标涉及一种称为翻译核糖体亲和纯化的细胞特异性RNA测序技术 (陷阱)。此外，目标2将描述小胶质细胞中Toll/nod样受体活性增加如何授予 对应激诱导的抑郁的敏感性，并作为BDPP代谢物的最接近的生物靶点。 最后，我们展示了BDPP代谢物如何阻止NAC中适应性不良的谷氨酸能突触的产生 通过调节MSN中突触基因的表达来应对应激。我们还表明，外周血中的IL-6 外周血白细胞对应激反应的产生是促进异常突触形成的关键 南华早报。因此，最终的目标将是进行无偏见的筛选，以确定其分子生物活性。 用TRAP方法检测D2 MSN中BDPP代谢物的变化，并探讨IL-6是否通过外周扩散进入 大脑通过IL-6R激活小胶质细胞，影响NAC突触密度的调节。这将提供一个 植物补充剂抑制外周血IL-6可促进弹性行为的机制 为将来的临床试验做准备。项目1将共同验证与以下因素相关的病理生理反应 IL-6可以被植物补充剂抑制，以促进对压力的弹性。