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: 10200686
• 负责人: Giulio Maria Pasinetti
• 金额: $ 45.01万
• 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/10200686
• 关键词: Acids; Address; Affect; Affinity Chromatography; Behavior; Behavioral; Bioavailable; Biological; 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; Gene Proteins; 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; Receptor Gene; Regulation; Ribosomes; Stimulus; Stress; Structure; Supplementation; Synapses; Techniques; Translating; Tumor-infiltrating immune cells; Up-Regulation; Work; base; blood-brain barrier function; blood-brain barrier permeabilization; cytokine; density; depression model; depressive behavior; endothelial dysfunction; immune function; immunoregulation; monocyte; neurovascular injury; polyphenol; prevent; psychologic; receptor; relating to nervous system; resilience; resilient behavior; response; social; social stress; symptomatology; synaptogenesis; 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 的目标是确定植物补充剂具有抵抗压力引起的能力 导致对抑郁行为易感性的病理生理反应。本提案将调查 生物活性膳食多酚制剂 (BDPP) 的多酚代谢物如何参与生物分子和 小胶质细胞、中型棘神经元 (MSN) 和血脑屏障 (BBB) 细胞中的遗传靶点，以促进 神经元功能和行为应对压力的弹性。最近的研究表明，功能失调 免疫活动通过影响上述细胞的活动而赋予对压力的易感性。系统性 在模型中观察到应激导致炎症细胞因子，特别是白细胞介素 6 (IL-6) 上调 抑郁症系统以及重度抑郁症患者。来自涉及经过验证的模型的初步研究 对于社会压力，我们发现白细胞持续表达 IL-6 仅在压力下影响 BBB 功能 易感小鼠。我们提供的证据表明 BDPP 生物可利用的代谢物可以提高社会适应能力 通过抑制细胞因子的产生来产生压力，这与维持血脑屏障完整性有关。我们的第一个 因此，我们的目标是确定 BDPP 是否能够通过靶向治疗来提供针对压力诱发抑郁症的恢复力 与 BBB 功能相关的机制。这一目标将决定植物补充剂是否可以预防 BBB 通透性和外周免疫因子通过神经内皮的浸润，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 补充 BDPP 可抑制应激诱导的小胶质细胞超分支和上调 炎症基因，与应激敏感性相关。我们的第二个目标是开展 无偏筛选以确定小胶质细胞中 BDPP 代谢物响应应激的分子生物活性。 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 样受体活性的增加如何赋予 对压力引起的抑郁症的易感性，并作为 BDPP 代谢物的近似生物靶标。 最后，我们展示了 BDPP 代谢物如何防止 NAc 中适应不良的谷氨酸突触生成 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IL-6 外周白细胞响应应激而产生的物质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筛选，以确定分子生物活性 使用 TRAP 方法研究 D2 MSN 中的 BDPP 代谢物，并研究外周 IL-6 是否扩散到 大脑通过 IL-6R 激活小胶质细胞，从而调节 NAc 突触密度。这将提供一个 为什么植物补充剂抑制外周 IL-6 可以促进弹性行为的机制 用于未来的临床试验。项目 1 将共同验证与以下因素相关的病理生理反应： IL-6 可以通过植物补充剂来抑制，以增强抗压能力。