Cancer prevention and treatment by activation of a brain-adipocyte axis

项目摘要 环境因素和生活方式对大学生心理健康的启动、促进和发展有着深刻的影响 癌症的进展。我们在环境浓缩(EE)方面的工作，这是一种住房环境 促进心理健康，揭示了一种新的表型，其特征是 肥胖，对饮食诱导的肥胖的抵抗，较低的瘦素水平，较高的脂联素水平， 增强免疫功能，显著抑制黑色素瘤、乳腺癌和结肠癌 成长。从机制上讲，EE提供的身体、社会和认知刺激刺激 下丘脑脑源性神经营养因子(BDNF)表达，从而激活 特异性神经内分泌轴、下丘脑-交感神经-脂肪细胞(HSA)轴导致 抑制瘦素的表达和释放，以及白色脂肪褐变。EE还可以增强T 细胞免疫通过交感神经系统(SNS)和下丘脑-垂体- 肾上腺(HPA)轴。代谢调节和免疫调节都有助于抗肿瘤。 EE和的作用由下丘脑BDNF协调。此外，我们初步的 数据表明，EE诱导脂肪驻留的自然杀伤(NK)细胞可能也是通过 HSA轴。这个项目的长期目标是调查生活方式和环境 调节脂肪免疫细胞的发育和功能的因素及其在 癌症防治。我们建议测试我们的假设，即环境和 HSA轴的基因激活通过脂肪细胞来源诱导脂肪驻留的NK细胞 白介素15，可能对癌症具有预防和治疗意义。我们计划 EE对脂肪NK细胞的调节作用及其机制的研究 目的1.具体地说，HSA轴的作用将通过两种遗传(拮抗)来研究 下丘脑脑源性神经营养因子信号转导)和药理学途径(β-肾上腺素能受体激动剂 或敌手)。为了评估脂肪细胞IL-15是否是血管紧张素转换酶的关键下游介质 提出脑-脂肪细胞-NK轴，我们将使用我们的新型脂肪特异性重组腺病毒- 联合病毒载体在脂肪细胞中过表达或敲除IL-15。此外， 我们将研究EE诱导的脂肪NK细胞对糖尿病的预防和治疗作用。 MMTV-PYMT自发模型及原位和转移性乳腺肿瘤 AIM 2中的乳腺癌移植模型。这些研究将进一步表征 脑介导的抗癌作用，确定一个新的脑-脂肪细胞-免疫轴连接 对物理和社会环境的有益适应性反应，并提供临床前 评估最终临床干预的可能性的数据。

Project Summary Environmental factors and lifestyle have profound effects in the initiation, promotion and progression of cancer. Our work on environmental enrichment (EE), a housing environment boosting mental health, has revealed a novel phenotype characterized by a robust reduction in adiposity, resistance to diet-induced obesity, lower leptin level, higher adiponectin level, enhanced immune functions, and marked inhibition in melanoma, breast, and colon cancer growth. Mechanistically, the physical, social and cognitive stimulations provided in EE stimulate hypothalamic brain-derived neurotrophic factor (BDNF) expression and thereby activates a specific neuroendocrine axis, hypothalamic-sympathoneural-adipocyte (HSA) axis leading to inhibition of leptin expression and release, as well as white fat browning. EE also enhances T cell immunity via both sympathetic nervous system (SNS) and the hypothalamic-pituitary- adrenal (HPA) axis. Both of the metabolic and immune modulations contribute to the antitumor effects of EE, and are orchestrated by the hypothalamic BDNF. Furthermore, our preliminary data suggest that EE induces adipose-resident natural killer (NK) cells likely also mediated by the HSA axis. The long-term goal of this project is to investigate how lifestyle and environmental factors regulate the development and function of adipose immune cells, and their implications in cancer prevention and treatment. We propose to test our hypothesis that environmental and genetic activation of the HSA axis induces adipose-resident NK cell through adipocyte-derived interleukin 15, which may have preventive and therapeutic significance of cancer. We plan to characterize the EE-induced regulation of adipose NK cells and elucidate the mechanisms in Aim 1. Specifically, the role of HSA axis will be investigated by both genetic (antagonizing hypothalamic BDNF signaling) and pharmacological approaches (β-adrenergic receptor agonist or antagonist). To assess whether adipocyte IL-15 is the key downstream mediator of the proposed brain-adipocyte-NK axis, we will use our novel adipose-specific recombinant adeno- associated viral vector to overexpress or knockdown IL-15 specifically in adipocytes. Moreover, we will study the preventive and therapeutic effects of EE-induced adipose NK cells on mammary tumor in the MMTV-PyMT spontaneous model as well as orthotopic and metastatic transplantation models of breast cancer in Aim 2. These studies will further characterize the brain-mediated anticancer effects, identify a novel brain-adipocyte-immune axis linking the beneficial adaptive responses to physical and social environments, and provide the preclinical data to assess the potential for ultimate clinical intervention.