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.

该职业发展奖将建立西米·福斯特（Simmie Foster）博士，成为专门研究的临床科学家 在抑郁症的背景下免疫的温度调节。福斯特博士拥有重要的基础科学专业知识 炎症和神经免疫性，尤其是在鼠标模型中，现在希望成为一个 面向患者的研究人员，研究人类受试者和组织。为了实现这一目标，她已经确定 几个培训目标：1）在进行以患者为导向的研究的方法方面发展专业知识， 包括新颖的研究设计和高级统计分析； 2）进一步的临床和研究培训 热疗的机制和应用； 3）培训收集，处理和解释 人类受试者中的免疫和物理生物标志物对理解作用机制至关重要 热疗； 4）进一步培训随机对照试验的负责行为。她有 组建了一个专家团队，指导她进行临床试验设计，高温敏感性和治疗以及 人体组织的表型。理由：系统性炎症反应对感染或 受伤是发烧。然而，温度调节和免疫之间的分子联系尚不清楚。提升 体温到发烧范围即使没有明显的免疫刺激，也已被证明可以改善 多种疾病，尤其是患有炎症基础的疾病，包括精神疾病，例如主要的疾病 抑郁症（MDD）。在此提案中，福斯特博士计划了一种多层次的方法，以调查如何 免疫细胞的热感应有助于暴露后观察到的炎症特征 高温，特别是温度升高对炎性体激活的后果。 反馈调节的候选目标是IL-1，典型的促炎细胞因子和内生源 热原（发烧诱导者）。伍尔夫实验室和其他实验室表明，热敏感的神经元与 免疫细胞调节注射，表明热感应可能在抑制IL-1的抑制中起作用 因此有助于高温对炎症性疾病的有益作用。在AIM 1中，她测试 整个身体高温诱导的抗炎反应的预测以诱导为特征 热休克蛋白和对重度抑郁症患者的炎性体介导的IL-1的抑制 紊乱。在AIM 2中，使用来自健康受试者的外周血单核细胞，她通过 暴露于温度升高会抑制炎症体。检验巨噬细胞的假设 通过神经元传感器传感升高温度会抑制IL-1的产生和加工。目标 3，使用免疫细胞神经元共培养，她确定了神经元热敏感性对变化的贡献 免疫细胞产生的炎症介质。这项研究的结果将导致更完整 抑郁症患者中高温治疗如何改变炎症性的图片，将是 广泛适用于了解温度如何调节炎症性疾病中的感染。