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: 10671048
• 负责人: Giulio Maria Pasinetti
• 金额: $ 44.14万
• 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/10671048
• 关键词: Acids; Address; Affect; Affinity Chromatography; Behavior; Behavioral; Biological; Biological Availability; Biological Models; Blood - brain barrier anatomy; Blood Vessels; Botanical dietary supplements; Brain; Brain region; Cells; Clinical; Clinical Trials; Complex; Cytokine Gene; Depressed mood; Dietary Polyphenol; Diffusion; Dyes; Endothelial Cells; Event; Excitatory Synapse; Exposure to; Functional disorder; Future; Gene Expression; Gene Expression Profile; Generations; Genes; Genetic; Glutamates; Goals; Homeostasis; Immune; Immune response; Immunologic Factors; Immunosuppression; Impairment; Infiltration; Inflammasome; Inflammatory; Interleukin 6 Receptor; Interleukin-1 beta; Interleukin-6; Knock-in; Leukocytes; Maintenance; Major Depressive Disorder; Mental Depression; Methods; Microglia; Modeling; Molecular; Molecular Target; Morphology; Mus; Neurons; Neurophysiology - biologic function; Nucleus Accumbens; Patients; Peripheral; Physiological; Plasma; Predisposition; Preparation; Production; Proteins; Receptor Gene; Regulation; Ribosomes; Stimulus; Stress; Structure; Supplementation; Synapses; Techniques; Translating; Up-Regulation; Work; blood-brain barrier function; blood-brain barrier permeabilization; cytokine; depression model; depressive behavior; endothelial dysfunction; immune cell infiltrate; immune function; immunoregulation; monocyte; neural; neurovascular injury; polyphenol; prevent; promote resilience; psychologic; receptor; resilience; resilient behavior; response; social; social stress; symptomatology; synaptogenesis; synergism; transcriptome; transcriptome sequencing; Acids; Address; Affect; Affinity Chromatography; Behavior; Behavioral; Biological; Biological Availability; Biological Models; Blood - brain barrier anatomy; Blood Vessels; Botanical dietary supplements; Brain; Brain region; Cells; Clinical; Clinical Trials; Complex; Cytokine Gene; Depressed mood; Dietary Polyphenol; Diffusion; Dyes; Endothelial Cells; Event; Excitatory Synapse; Exposure to; Functional disorder; Future; Gene Expression; Gene Expression Profile; Generations; Genes; Genetic; Glutamates; Goals; Homeostasis; Immune; Immune response; Immunologic Factors; Immunosuppression; Impairment; Infiltration; Inflammasome; Inflammatory; Interleukin 6 Receptor; Interleukin-1 beta; Interleukin-6; Knock-in; Leukocytes; Maintenance; Major Depressive Disorder; Mental Depression; Methods; Microglia; Modeling; Molecular; Molecular Target; Morphology; Mus; Neurons; Neurophysiology - biologic function; Nucleus Accumbens; Patients; Peripheral; Physiological; Plasma; Predisposition; Preparation; Production; Proteins; Receptor Gene; Regulation; Ribosomes; Stimulus; Stress; Structure; Supplementation; Synapses; Techniques; Translating; Up-Regulation; Work; blood-brain barrier function; blood-brain barrier permeabilization; cytokine; depression model; depressive behavior; endothelial dysfunction; immune cell infiltrate; immune function; immunoregulation; monocyte; neural; neurovascular injury; polyphenol; prevent; promote resilience; psychologic; receptor; resilience; resilient behavior; response; social; social stress; symptomatology; synaptogenesis; synergism; transcriptome; transcriptome sequencing

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的目的是确定植物补充剂为压力引起的弹性提供了弹性 病理生理反应赋予对抑郁行为的敏感性。该提议将调查 生物活性饮食多酚制剂（BDPP）的多酚代谢产物如何参与生物分子和 小胶质细胞，中棘神经元（MSN）和血脑屏障（BBB）细胞的遗传靶标 响应压力的神经元功能和行为的弹性。最近的研究表明功能失调 免疫活性通过影响上述细胞的活性来赋予对压力的敏感性。系统性 在模型中观察到炎性细胞因子的上调，特别是白介素-6（IL-6） 抑郁症系统以及MDD患者。来自涉及经过验证模型的初步研究 在社会压力下，我们表明白细胞的持续性IL-6表达仅影响BBB的功能 - 易感小鼠。我们提供证据表明BDPP生物利用代谢物可能会促进对社会的韧性 通过抑制细胞因子的产生，这与维持BBB完整性有关。我们的第一个 因此，目标是确定BDPP是否通过靶向压力引起的抑郁症提供了弹性 与BBB功能相关的机制。这个目标将决定植物补充剂是否阻止 BBB的渗透性和通过神经内皮细胞的外周免疫因子浸润，并将 表征内皮细胞中BDPP代谢物的生物分子靶标。我们的初步研究表明 BDPP补充抑制了应力诱导的小胶质细胞过度涂抹和上调 炎症基因，与应激敏感性有关。我们的第二个目标是进行 无偏见的筛查以鉴定小胶质细胞中BDPP代谢产物的分子生物活性响应应力。 此目的涉及一种细胞特异性的RNA测序技术，该技术称为翻译核糖体亲和力纯化 （陷阱）。此外，AIM 2将表征小胶质细胞会议中TOLL/NOD类受体的活性增加 对压力诱导的抑郁症的敏感性，并充当BDPP代谢产物的近端生物学靶标。 最后，我们展示了BDPP代谢物如何防止适应不良的谷氨酸能突触在NAC中的发作 通过调节MSN中突触基因的表达对压力的反应。我们还表明外围IL-6 外周白细胞响应压力而产生的生产对于促进异常突触形成至关重要 NAC。因此，最终目标是进行公正的屏幕以识别分子生物活性 D2 MSN中的BDPP代谢产物使用陷阱方法，并研究外周三体IL-6扩散是否 大脑通过IL-6R激活小胶质细胞，以实现NAC突触密度的调节。这将提供一个 为什么通过植物补充剂抑制外围IL-6的机制可以促进弹性行为 为将来的临床试验。项目1一起将验证与 IL-6可以通过植物补充剂来抑制以促进压力的弹性。