Assessment of Mechanisms Underlying B Cell Impacts on Resilience and Susceptibility to Stress

评估 B 细胞对压力的恢复力和敏感性的影响机制

• 批准号: 9892178
• 负责人: Elizabeth Engler-Chiurazzi
• 金额: $ 14.62万
• 依托单位: WEST VIRGINIA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-12-01 至 2020-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9892178
• 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.

项目总结/摘要 免疫系统作为情绪的关键调节器的出现为免疫系统提供了新的机会。 治疗使人衰弱的心理健康障碍，如重度抑郁症。然而，虽然融合数据意味着- 评估过度的促炎级联反应和T细胞过度活化在发展和持续性 MDD和B淋巴细胞之间的关系尚未得到很好的研究，这使得我们的研究存在空白。 关于抑郁症免疫理论的知识。几项发现强调了B细胞在肿瘤中的关键作用。 对压力的反应和调节情绪，包括初步数据暗示B细胞缺乏与一个mala- 对急性强迫游泳应激的适应性反应，这种反应通过免疫调节得到改善。 因此，B细胞可能在应激反应和情绪中发挥关键作用，但尚未得到很好的描述。 这一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，本提案的目的是通过以下方式定义机制： 哪些B细胞调节应激反应，并支持申请人成为独立的R 01- 在心理健康领域的资助调查员，在大脑功能和脑功能的免疫调节方面具有专业知识， 或这项研究的关键下一步是系统地确定B细胞控制的机制。 心情该建议的中心假设是B细胞的免疫调节作用维持了抵抗力， 通过分泌免疫抑制细胞因子白细胞介素-10来缓解压力。为了测试这个有希望的- 假设，B细胞在应激反应和情绪相关神经基质中的作用将得到验证 使用体内B细胞耗竭（Aim 1）。接下来，使用缺乏调节性但没有其他B细胞的小鼠，或者 B细胞缺乏无法分泌白细胞介素-10，这是B细胞免疫调节机制影响细胞的潜力 出现适应压力引起的适应不良行为模式，并显示其他异常， 将评估MDD（目标2）。最后，B积累和释放白细胞介素-10，在中枢神经系统 将对目标部位进行评价（目标3）。完成这些研究和培训将有助于发展 申请人的独立研究计划，为继续探索这一点提供证据基础。 题目，提高竞争力，为成功获得校外资助。事实上，数据生成- 艾德在这里将提供深入了解机制参与B细胞控制情绪和弹性与suscep。 对急性和慢性压力的稳定反应。在这样做的时候，这个建议将推进申请人的职业目标， 提供额外的洞察机制的弹性和敏感性的压力，对posi- 作为一名富有成效的科学家，积极影响心理健康领域，帮助改善临床实践， 研究新的治疗目标和方法，最终减轻情绪障碍的负担。