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.

项目摘要/摘要 免疫系统作为情绪的关键调节器的出现为人们发现了新的机会 治疗严重抑郁症等衰弱的精神健康障碍。然而，尽管融合的数据意味着- 慢性粒细胞白血病发生和持续过程中过度的促炎性级联反应和T细胞过度激活 MDD与B淋巴细胞之间的关系还没有得到很好的研究，这在我们的研究中留下了空白 有关抑郁症免疫理论的知识。一些发现强调了B细胞在人类免疫缺陷中的关键作用。 对压力和调节情绪的反应，包括初步数据表明B细胞缺乏症与疟疾有关- 对急性强迫游泳压力的反应，这种反应通过免疫调节得到了改善。 因此，B细胞可能在应激反应和情绪中扮演着关键的角色，但还没有被很好地描述出来。 这个新兴领域令人兴奋的潜力塑造了申请者的长期研究目标：阐明 免疫系统调节控制大脑功能的神经生物底物的机制。AS B细胞对大脑的影响还不是很清楚，这项提议的目的是通过以下方式来定义机制 哪些B细胞调节应激反应并支持申请者成为独立的R01- 资助精神健康领域的研究人员，拥有大脑功能和行为免疫调节方面的专业知识- IOR。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。这一建议的中心假设是，B细胞的免疫调节作用维持在正常范围内。 通过分泌免疫抑制细胞因子白介素10来应对压力。为了测试这个有希望的HY- 假设，B细胞在应激反应和与情绪相关的神经底物中的作用将得到验证 使用体内B细胞去除(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 B细胞缺乏不能分泌白介素10的能力，这是B细胞免疫调节机制影响T细胞功能的潜在因素。 观察应激诱导的适应不良行为模式，并表现出其他异常 将评估千年发展目标(目标2)。最后，B细胞在中枢神经系统的蓄积和释放 将对目标地点进行评估(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 主题和提高竞争力，以成功地获得外部资金。事实上，数据生成- ED在这里将深入了解B细胞控制情绪的机制，以及弹性与休眠- 对急性和慢性压力的快速反应。通过这样做，这项建议将使申请者的职业目标提前到 提供对压力源的恢复力和易感性的潜在机制的更多洞察，以定位 作为一名多产的科学家，对心理健康领域产生了重大影响，以帮助改善临床实践 每一个新的治疗目标和方法，并最终减轻情绪障碍的负担。