Inflammatory signaling in depression regulated by Toll-like receptors 2 and 4

Toll 样受体 2 和 4 调节抑郁症中的炎症信号传导

• 批准号: 10083684
• 负责人: RICHARD S. JOPE
• 金额: --
• 依托单位: MIAMI VA HEALTH CARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-01-01 至 2021-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10083684
• 关键词: Acute; Address; Affect; Agonist; Animal Model; Anti-Inflammatory Agents; Antidepressive Agents; Behavior; Behavior assessment; Brain-Derived Neurotrophic Factor; Cardiovascular Diseases; Characteristics; Clinical; Development; Disease; Equilibrium; General Population; Health; Homeostasis; Immune system; Impairment; Individual; Infection; Inflammation; Inflammatory; Inflammatory Response; Knock-out; Knockout Mice; Learned Helplessness; Left; Maintenance; Major Depressive Disorder; Malignant Neoplasms; Measures; Mediating; Mental Depression; Modality; Modeling; Moods; Mus; Pharmaceutical Preparations; Pharmacology; Population; Predisposition; Prognosis; Proteins; Recovery; Reporting; Research Personnel; Resistance; Severities; Signal Pathway; Signal Transduction; Stress; Symptoms; System; TLR2 gene; TLR4 gene; Tail Suspension; Testing; Therapeutic Effect; Time; United States; Veterans; Weight; base; behavior test; behavioral outcome; comorbidity; cytokine; depression model; depressive symptoms; drug development; improved; innovation; mood regulation; mouse model; mouse toll-like receptor 2; mouse toll-like receptor 4; new therapeutic target; novel; novel strategies; novel therapeutics; preclinical study; receptor; response; success; therapeutic target; therapy development

The objective of this project is to determine how inflammatory signaling by Toll-like receptor-2 (TLR2) and TLR4 regulate depression-like behaviors in mice to develop new therapeutic targets for major depression. This exciting possibility is based on our novel Preliminary Results showing that TLR4 signaling increases susceptibility to depression onset modeled in mice, whereas TLR2 signaling promotes recovery from depression. These balancing mood-regulating actions of inflammatory receptors typifies the immune system characteristic of balancing signals in order to respond to damage or infection, but limiting the response to avoid damage to the host. This is an important subject because major depression is highly prevalent and debilitating in veterans, and therapies are often not adequate. Novel targets need to be identified to develop new therapies, and the inflammatory system is one such novel target, as substantial evidence demonstrates inflammatory activation promotes depression. We also propose that drug development may have been limited by a primary focus on modulating onset in animal models, whereas recovery from depression is equally important for therapy development. By giving equal weight to examining susceptibility and recovery and examining receptors that mediate inflammatory signaling, our Preliminary Results demonstrate that TLR4 promotes onset and TLR2 provides the balance by promoting recovery from depression. Our overall hypothesis is that TLR-mediated signals regulate maintenance of mood homeostasis, whereas abnormalities in TLR actions promote the development and prolongation of depression. Testing this hypothesis will establish the potential for drugs acting on TLR2 and TLR4 to bolster resistance to depression and support recovery. Specific Aim 1 will test the hypothesis that TLR2 and TLR4 oppositely regulate depression-like behavior in mice. A panel of behavioral assessments widely used to model depression-like behaviors will be applied to TLR2 and TLR4 knockout mice, with and without antidepressant treatment, examining both onset and recovery. Specific Aim 2 will test behavioral outcomes of pharmacologically modulating TLR2 and TLR4. We will test the hypothesis that TLR2 agonists and TLR4 antagonists are antidepressant. Specific Aim 3 will test mechanisms that regulate recovery from depressive-like behavior. We will test mechanisms that regulate signaling involved in recovery from depression, such as cytokines and brain-derived neurotrophic factor (BDNF), and examine proteins reported to be involved in mood regulation, to identify those critical for the pro-depressant effect of TLR4 stimulation and depression-recovery facilitating effect of TLR2 stimulation. Altogether this is an innovative project examining TLR2/4 as feasible therapeutic targets to reduce the susceptibility and duration of depression modeled in mice, an important problem affecting the health of many veterans.

该项目的目的是确定如何通过Toll样受体2（TLR2）进行炎症信号传导 和TLR4调节小鼠的抑郁症行为，以开发主要的主要治疗靶标 沮丧。这种令人兴奋的可能性是基于我们新颖的初步结果表明TLR4 信号传导增加了对小鼠建模的抑郁症发作的敏感性，而TLR2信号传导 促进抑郁症的恢复。这些平衡的炎症受体的情绪调节作用 代表平衡信号的免疫系统特征，以应对损害或感染， 但是，限制响应以避免对主机的损害。这是一个重要的主题，因为专业 抑郁症高度流行，在退伍军人中使人衰弱，疗法通常不够。小说 需要确定目标以开发新疗法，而炎症系统就是这样一种新颖的 靶标，正如大量证据表明炎症激活会促进抑郁症。我们也是 建议药物开发可能受到调节动物发作的主要重点的限制 模型，而从抑郁症中恢复对治疗的发展同样重要。通过相等 重量检查易感性和恢复和检查介导炎症的受体 信号传导，我们的初步结果表明TLR4促进了发作，而TLR2提供了 通过促进抑郁症的恢复来平衡。我们的总体假设是TLR介导的信号 调节情绪稳态的维持，而TLR行动中的异常促进 抑郁症的发展和延长。检验该假设将确定药物的潜力 作用于TLR2和TLR4，以增强对抑郁的抵抗并支持恢复。具体目标1将 检验了TLR2和TLR4相对调节小鼠抑郁样行为的假设。一个面板 行为评估广泛用于模拟类似抑郁症的行为的行为将应用于TLR2和 TLR4敲除小鼠，有或没有抗抑郁药治疗，检查了发作和恢复。 特定的目标2将测试对TLR2和TLR4进行药理调节的行为结果。我们将 检验TLR2激动剂和TLR4拮抗剂是抗抑郁药的假设。特定目标3将测试 调节抑郁样行为恢复的机制。我们将测试调节的机制 从抑郁症中恢复的信号传导，例如细胞因子和脑衍生的神经营养因子 （BDNF），并检查据报道参与情绪调节的蛋白质，以识别那些对 TLR4刺激和抑郁恢复的促抑制作用促进TLR2刺激的作用。 总之，这是一个创新的项目，研究TLR2/4作为可行的治疗目标，以减少 在小鼠中建模的抑郁症的敏感性和持续时间，这是一个影响健康健康的重要问题 许多退伍军人。