Peripheral Neuroimmune Mechanisms of Hyperthermia

热疗的周围神经免疫机制

• 批准号: 10241977
• 负责人: Simmie Foster
• 金额: $ 19.62万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10241977
• 关键词: Anti-Inflammatory Agents; Antidepressive Agents; Basic Science; Biological Markers; Body Temperature; Brain; Capsaicin; Cells; Chronic Disease; Clinical Research; Clinical Trials Design; Coculture Techniques; Collection; Development; Disease; Dose; Ethnic Origin; Exposure to; Feedback; Fever; Fostering; Future; General Population; Genes; Genetic Transcription; Genotype; Goals; Heat shock proteins; Heat-Shock Response; Homeostasis; Hyperthermia; Hypothalamic structure; Immune; Immunity; In Vitro; Induced Hyperthermia; Infection; Inflammasome; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Response; Injury; Interleukin-1; Interleukin-6; K-Series Research Career Programs; Lead; Link; Major Depressive Disorder; Measures; Mediating; Membrane; Mental Depression; Mental disorders; Methodology; Microglia; Molecular; Multienzyme Complexes; Neuroimmunomodulation; Neurons; Neuropeptides; Pathway interactions; Patients; Peripheral; Phagocytes; Pharmacology Study; Phenotype; Physiologic Thermoregulation; Physiological; Plasma; Play; Production; Property; Protein Inhibition; Randomized Controlled Trials; Regulation; Research Design; Research Personnel; Role; Scientist; Septic Shock; Serum; Statistical Data Interpretation; Stimulus; TRPV1 gene; Temperature; Testing; Tissues; Training; Woman; cytokine; depressed patient; depressive symptoms; design; endogenous pyrogen; endoplasmic reticulum stress; exercise intensity; human subject; human tissue; hyperthermia treatment; induced pluripotent stem cell; macrophage; men; monocyte; mouse model; novel; patient oriented; patient oriented research; peripheral blood; physiologic model; recruit; response; sensor; sulfated glycoprotein 2; systemic inflammatory response

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.

该职业发展奖将使 Simmie Foster 博士成为一名专门从事以下领域的临床医生-科学家： 抑郁症下免疫的温度调节。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，现在希望成为一名 以患者为中心的研究人员，研究人体受试者和组织。为了实现这一目标，她确定了 几个培训目标：1）发展以患者为导向的研究方法方面的专业知识， 包括新颖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）收集、处理和解释培训 人类受试者的免疫和生理生物标志物对于理解其作用机制至关重要 体温过高； 4) 负责任地进行随机对照试验的进一步培训。她有 组建了一个专家团队来指导她进行临床试验设计、热疗传感和治疗，并 人体组织的表型分析。理由：对感染或感染的全身炎症反应的标志 受伤就是发烧。然而，体温调节和免疫之间的分子联系仍不清楚。提升 即使没有明显的免疫刺激，体温到发烧的范围也已被证明可以改善 多种疾病，特别是那些具有炎症基础的疾病，包括精神疾病，例如严重的 抑郁症（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如何 免疫细胞的热感应有助于在暴露于环境后观察到的炎症特征 体温过高，特别是温度升高对炎症小体激活的影响。 反馈调节的候选目标是 IL-1，典型的促炎细胞因子和内源性细胞因子。 热原（发烧诱导物）。伍尔夫实验室和其他人已经表明，热敏神经元与 免疫细胞调节炎症，表明热感应可以在抑制 IL-1 中发挥作用， 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 预测全身高温会诱导以诱导为特征的抗炎反应 重度抑郁症患者热休克蛋白的表达和炎症小体介导的 IL-1 的抑制 紊乱。在目标 2 中，她使用健康受试者的外周血单核细胞，通过以下方式剖析了机制： 暴露于高温会抑制炎症小体；检验巨噬细胞的假设 通过神经元传感器感知升高的温度会抑制 IL-1 的产生和加工。瞄准 3，使用免疫细胞神经元共培养，她确定了神经元热感应对变化的贡献 免疫细胞产生的炎症介质。这项研究的结果将带来更完整的 热疗治疗如何改变抑郁症患者的炎症状况的图片，并将 广泛适用于了解温度如何调节炎症性疾病中的炎症。