Assessment of mechanisms underlying B cell impacts on resilience and susceptibility to stress

评估 B 细胞对压力恢复力和敏感性的影响机制

• 批准号: 10388262
• 负责人: Elizabeth Engler-Chiurazzi
• 金额: $ 14.33万
• 依托单位: TULANE UNIVERSITY OF LOUISIANA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-12-01 至 2023-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10388262
• 关键词: Acute; Address; Adopted; Anti-Inflammatory Agents; Antidepressive Agents; B-Cell Development; B-Lymphocytes; Behavior; Behavior assessment; Behavioral; Biological; Blood - brain barrier anatomy; Brain; Cell Count; Cells; Chronic stress; Corticosterone; Data; Development; Evaluation; Extramural Activities; Female; Funding; Goals; Growth Factor; Homeostasis; Hormones; Human; Immune; Immune system; Interleukin-10; Knowledge; Major Depressive Disorder; Mental Depression; Mental Health; Mental disorders; Mentors; Monitor; Mood Disorders; Moods; Mus; Neuraxis; Neurobiology; Outcome; Outcome Study; Pathologic; Patients; Pattern; Peripheral; Phenotype; Play; Predisposition; Property; Research; Research Personnel; Rodent; Role; Scientist; Site; Stress; Suggestion; Swimming; T-Cell Activation; T-Lymphocyte; Testing; Tissues; Training; acute stress; biological adaptation to stress; brain parenchyma; career; cell motility; clinical practice; cytokine; experimental study; humoral immunity deficiency; immunoregulation; improved; in vivo; innovation; insight; male; mind control; monoamine; neuropsychiatric disorder; new therapeutic target; novel; patient response; programs; relating to nervous system; resilience; response; stress resilience; stressor; theories; therapeutic target; tool; trafficking

PROJECT SUMMARY/ABSTRACT The emergence of the immune system as a key regulator of mood identifies novel opportunities for the treatment of debilitating mental health disorders such as major depression. Yet, while converging data impli- cate excessive proinflammatory cascades and T cell overactivation in the development and persistence of MDD, the relationship between MDD and B lymphocytes has not been well studied leaving a gap in our knowledge regarding the immune theory of depression. Several findings highlight key roles for B cells in the response to stress and modulating mood, including preliminary data implicating B cell deficiency with a mala- daptive response to acute forced swim stress, a response that was ameliorated with immune modulation. Thus, B cells may play a critical, but not well delineated, role on the stress response and mood. The exciting potential of this burgeoning field has shaped the applicant’s long-term research goal: to elucidate mechanisms by which the immune system regulates neurobiological substrates that control brain function. As B cell impacts on the brain are not well known, the objective of this proposal is to define the mechanisms by which B cells modulate the stress response and to support the applicant to become an independent, R01- funded investigator in the mental health field with expertise in immune regulation of brain function and behav- ior. The crucial next step in this research is to systematically identify mechanisms by which B cells control mood. The central hypothesis of this proposal is that the immunoregulatory action of B cells maintains resili- ence from stress via secretion of the immunosuppressive cytokine, interleukin-10. To test this promising hy- pothesis, the role of the B cell on the stress response and associated neural substrates of mood will be verified using in vivo B cell depletion (Aim 1). Next, using mice that lack regulatory but not other B cells, or mice whose B cells lack cannot secrete interleukin-10, the potential for immunomodulatory mechanisms of B cells to influ- ence the adaptation of a stress-induced maladaptive behavioral pattern and display other abnormalities seen in MDD will be assessed (Aim 2). Finally, B accumulation and release of interleukin-10, at central nervous system target sites will be evaluated (Aim 3). Completion of these studies and training will support the development of the applicant’s independent research program by providing the evidential basis for continued exploration of this topic and enhance competitiveness for the successful acquisition of extramural funding. Indeed, data generat- ed here will provide insight into mechanisms involved in B cell control of mood and the resilient versus suscep- tible response to acute and chronic stress. In doing so, this proposal will advance the applicant’s career goal to provide additional insight into the mechanisms underlying the resilience and susceptibility to stressors, to posi- tively impact the mental health field as a productive scientist, to help improve clinical practice with the discov- ery of new therapeutic targets and approaches, and ultimately, to ease the burden of mood disorders.

项目概要/摘要 免疫系统作为情绪关键调节剂的出现为免疫系统的出现提供了新的机会。 治疗严重抑郁症等使人衰弱的精神健康疾病。然而，虽然融合数据意味着 在炎症的发展和持续过程中引发过度的促炎级联反应和 T 细胞过度激活 MDD，MDD 和 B 淋巴细胞之间的关系尚未得到很好的研究，在我们的研究中留下了空白 有关抑郁症免疫理论的知识。多项研究结果强调了 B 细胞在 对压力的反应和调节情绪，包括涉及 B 细胞缺陷与马拉色菌的初步数据 对急性强迫游泳应激的适应性反应，这种反应可通过免疫调节得到改善。 因此，B 细胞可能对压力反应和情绪发挥着关键但尚未明确的作用。 这个新兴领域令人兴奋的潜力塑造了申请人的长期研究目标：阐明 免疫系统调节控制大脑功能的神经生物学底物的机制。作为 B 细胞对大脑的影响尚不清楚，该提案的目的是通过以下方式定义其机制： 哪些 B 细胞调节压力反应并支持申请人成为独立的人，R01- 资助心理健康领域的研究人员，具有脑功能和行为免疫调节方面的专业知识 或。这项研究的下一步关键是系统地确定 B 细胞控制的机制 情绪。该提议的中心假设是 B 细胞的免疫调节作用维持弹性 通过分泌免疫抑制细胞因子白细胞介素 10 来缓解压力。为了测试这个有前途的hy- 假设，B 细胞对应激反应和情绪相关神经基质的作用将得到验证 使用体内 B 细胞耗竭（目标 1）。接下来，使用缺乏调节但没有其他 B 细胞的小鼠，或者具有 B细胞缺乏不能分泌白细胞介素10，B细胞免疫调节机制的潜力 从而适应压力引起的适应不良行为模式，并表现出其他异常情况 将评估 MDD（目标 2）。最后，B在中枢神经系统中积累并释放白细胞介素10 将评估目标地点（目标 3）。完成这些研究和培训将支持发展 申请人的独立研究计划，为继续探索这一问题提供证据基础 主题并增强竞争力，以成功获得外部资金。事实上，数据生成 本文将深入了解 B 细胞控制情绪以及弹性与敏感性的机制。 对急性和慢性应激的反应。在此过程中，该提案将推动申请人的职业目标 提供对压力源的弹性和敏感性的机制的额外见解，以确保 作为一名富有成效的科学家积极影响心理健康领域，通过发现来帮助改善临床实践 一系列新的治疗目标和方法，最终减轻情绪障碍的负担。