Peripheral Neuroimmune Mechanisms of Hyperthermia

这一职业发展奖将使Simmie Foster博士成为一名临床医生兼科学家，专门从事 抑郁症背景下的免疫体温调节。福斯特博士在以下领域拥有重要的基础科学专业知识 炎症和神经免疫，特别是在小鼠模型中，现在希望成为一个 以病人为中心的研究人员，研究人类受试者和组织。为了实现这一目标，她确定了 几个培训目标：1)培养开展以患者为中心的研究的方法学专业知识； 包括新的研究设计和先进的统计分析；2)临床和研究方面的进一步培训 热疗的机制和应用；3)培训收集、处理和解释 人体免疫和生理生物标记物对了解心绞痛作用机制至关重要 体温过高；以及4)进一步培训负责任地进行随机对照试验。她有 组建了一个专家团队，指导她进行临床试验设计、体温监测和治疗，以及 人体组织的表型。基本原理：感染或感染引起的全身炎症反应的标志 受伤是发烧。然而，体温调节和免疫力之间的分子联系仍不清楚。提升 体温到发烧的范围，即使在没有明显的免疫刺激的情况下，也被证明是可以改善的。 多种疾病，特别是那些具有炎症性基础的疾病，包括严重的 抑郁障碍(MDD)。在这项提案中，福斯特博士计划采用多层次的方法来研究 免疫细胞的热感应有助于观察到暴露于 体温过高，特别是体温升高对炎症体激活的影响。 反馈调节的候选靶点是IL-1，它是典型的促炎细胞因子和内源性 热原(发烧诱导剂)。伍尔夫实验室和其他实验室已经表明，温度敏感的神经元与 免疫细胞调节炎症，表明热感应可能在抑制IL-1方面发挥作用， 从而有助于热疗对炎症性疾病的有益作用。在《目标1》中，她测试了 全身热疗诱导以诱导为特征的抗炎反应的预测 重度抑郁症患者热休克蛋白和炎症体介导的IL-1的抑制作用 无序。在目标2中，她使用健康受试者的外周血单核细胞，通过 哪个暴露在高温下能抑制炎症小体；测试巨噬细胞 通过神经元感应器感知温度升高会抑制IL-1的产生和处理。在AIM 3，利用免疫细胞与神经元的共同培养，她确定了神经元热感应对细胞变化的贡献 免疫细胞产生的炎症介质。这项研究的结果将导致更完整的 热疗如何改变抑郁症患者的炎症状态，并将 广泛适用于了解温度如何调节炎症性疾病中的炎症。

This career development award will establish Dr. Simmie Foster as a clinician-scientist specializing in thermoregulation of immunity in the context of depression. Dr. Foster has significant basic science expertise in inflammation and neuroimmunity, especially in mouse models, and now wishes to move towards becoming a patient-oriented researcher, studying human subjects and tissues. To accomplish this goal, she has identified several training objectives: 1) Develop expertise in the methodology to conduct patient-oriented research, including novel study design and advanced statistical analyses; 2) Further training in clinical and research mechanisms and applications of hyperthermia; 3) Training in collection, processing, and interpretation of immune and physiological biomarkers in human subjects critical to understanding the mechanisms of action of hyperthermia; and 4) Further training in the responsible conduct of randomized controlled trials. She has assembled an expert team to guide her in clinical trial design, hyperthermia sensing and treatment, and phenotyping of human tissues. Rationale: A hallmark of the systemic inflammatory response to infection or injury is fever. Yet the molecular links between thermoregulation and immunity remain unclear. Elevating the body temperature to fever range, even in the absence of overt immune stimuli, has been shown to ameliorate multiple ailments, especially those with an inflammatory basis, including psychiatric disease such as major depressive disorder (MDD). In this proposal, Dr. Foster plans a multi-level approach to investigate how heat-sensing by immune cells contributes to the inflammatory profile observed after exposure to hyperthermia, and specifically the consequences of elevated temperature on inflammasome activation. A candidate target for feedback regulation is IL-1, the prototypical proinflammatory cytokine and endogenous pyrogen (fever-inducer). The Woolf lab and others have shown that thermo-sensitive neurons interact with immune cells to regulate inflammation, indicating that heat sensing could play a role in inhibition of IL-1, and thus contribute to the beneficial effect of hyperthermia on inflammatory disease. In Aim 1, she tests the prediction that whole body hyperthermia induces an anti-inflammatory response characterized by induction of heat shock proteins and inhibition of inflammasome mediated IL-1 in patients with major depressive disorder. In Aim 2, using peripheral blood monocytes from healthy subjects, she dissects mechanisms by which exposure to elevated temperature inhibits the inflammasome; testing the hypothesis that macrophage sensing of elevated temperature through neuronal sensors inhibits production and processing of IL-1. In Aim 3, using immune cell neuronal co-cultures, she determines contribution of neuronal heat sensing to changes in inflammatory mediators produced by immune cells. The results of this study will lead to a more complete picture of how hyperthermia treatment changes the inflammatory profile in depressed patients, and will be broadly applicable to understanding how temperature regulates inflammation in inflammatory diseases.