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: 10302513
• 负责人: Elizabeth Engler-Chiurazzi
• 金额: $ 14.62万
• 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/10302513
• 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.

项目摘要/摘要 免疫系统作为情绪的关键调节者的出现确定了新的机会 治疗衰弱的心理健康障碍，例如严重抑郁症。但是，同时收敛数据暗示 猫在发育和持久性中超级促炎级联和T细胞过度活化 MDD，MDD和B淋巴细胞之间的关系并没有很好地研究我们 有关抑郁症免疫理论的知识。几个发现突出了B细胞在 对压力和调节情绪的响应，包括初步数据隐式B细胞缺乏症和mala- 对急性强迫游泳应力的急剧反应，这种反应通过免疫调节改善。 这是B细胞在压力反应和情绪中的作用，可能发挥关键但没有很好的描述。 这个新兴领域的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 B细胞调节应力反应并支持申请人成为独立的R01- 在心理健康领域的资助研究者具有对脑功能和行为的免疫调节的专业知识 ior。这项研究的关键下一步是系统地识别B细胞控制的机制 情绪。该提议的核心假设是，B细胞的免疫调节作用保持弹性 通过分泌免疫抑制细胞因子，白细胞介素10。测试这一诺言 将验证B细胞在应力反应和相关神经底物中的作用，将验证 使用体内B细胞耗竭（AIM 1）。接下来，使用缺乏调节的小鼠，而不是其他B细胞，或者使用的小鼠或 B细胞缺乏秘密白细胞介素10，这是B细胞的免疫调节机制的潜力 - 适应压力引起的适应不良行为模式，并显示出其他异常 将评估MDD（AIM 2）。最后，在中枢神经系统上，白细胞介素10的B积累和释放 目标站点将进行评估（AIM 3）。这些研究和培训的完成将支持 申请人的独立研究计划通过为继续探索的证据基础提供证据基础 主题并提高成功获得壁外资金的竞争力。确实，数据生成器 - ED此处将提供有关情绪B细胞控制的机制以及弹性与敏感的机制的见解。 对急性和慢性应激的可抗反应。通过这样做，该建议将使申请人的职业目标促进 提供对弹性和对压力源的敏感性的基础机制的更多见解，对压力源的敏感性 作为一名富有成效的科学家，对心理健康领域的影响，以帮助改善Discov的临床实践 赋予新的治疗靶标和方法，并最终减轻情绪障碍的燃烧。