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

通过激活脑-脂肪细胞轴来预防和治疗癌症

基本信息

批准号：
10317047
负责人：
Lei Cao
金额：
$ 36.31万
依托单位：
OHIO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-01-01 至 2024-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10317047
关键词：
Adipocytes Adipose tissue Adrenergic beta-Agonists Affinity Agonist Brain Brain-Derived Neurotrophic Factor Breast Cancer Model Brown Fat Cancer Patient Cancer Prevention Intervention Cells Clinical Cognitive Colon Carcinoma Data Development Diet Distal Environment Environmental Risk Factor Equilibrium Exercise Fatty acid glycerol esters Female Funding Gene Transfer Genetic Glioma Goals Growth Health High Fat Diet Homeostasis Housing Hypothalamic structure Immune Immunity Individual Insulin-Like Growth Factor I Interleukin-15 Intervention Knowledge Leptin Life Style Link Lymphoid Tissue Malignant Neoplasms Malignant neoplasm of pancreas Mammary Neoplasms Mediating Mediator of activation protein Mental Health Metabolic Modeling Mouse Mammary Tumor Virus Mus Natural Increases Natural Killer Cells Neurosecretory Systems Obesity Outcome Palpable Pharmacology Phenotype Physical environment Preventive Psychological Stress Recombinants Regulation Resistance Risk Role Serum Signal Transduction Social Environment Social isolation Social support Solid Neoplasm Sympathetic Nervous System T-Lymphocyte Testing Therapeutic Therapeutic Effect Thinness Transplantation Visceral fat Well in self Work adeno-associated viral vector adiponectin antagonist anti-cancer antitumor effect beta-adrenergic receptor biobehavior cancer prevention cancer therapy cell killing clinically relevant cytotoxic CD8 T cells diet-induced obesity energy balance environmental enrichment for laboratory animals epidemiology study glycemic control hypothalamic-pituitary-adrenal axis hypothalamic-sympathoneural-adipocyte axis immune function immunoregulation improved insight insulin sensitivity knock-down lifestyle factors malignant breast neoplasm mammary melanoma mortality novel overexpression pre-clinical prospective receptor response social social influence transplant model tumor progression tumor-immune system interactions

项目摘要

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.

项目概要环境因素和生活方式对启动、促进和我们在环境丰富 (EE)（住房环境）方面的工作。促进心理健康，揭示了一种新的表型，其特征是显着减少肥胖，对饮食引起的肥胖的抵抗力，瘦素水平较低，脂联素水平较高，增强免疫功能，对黑色素瘤、乳腺癌、结肠癌有显着抑制作用从机制上讲，EE 提供的身体、社交和认知刺激会刺激成长。下丘脑脑源性神经营养因子（BDNF）的表达和激活，从而特定的神经内分泌轴，下丘脑-交感神经-脂肪细胞（HSA）轴导致抑制瘦素表达和释放以及白色脂肪褐变也可增强 T。通过交感神经系统（SNS）和下丘脑-垂体-的细胞免疫肾上腺 (HPA) 轴的代谢和免疫调节都有助于抗肿瘤。 EE 的影响，并由下丘脑 BDNF 协调。数据表明，EE 诱导脂肪驻留的自然杀伤 (NK) 细胞也可能由以下因素介导： HSA 轴的长期目标是调查生活方式和环境之间的关系。调节脂肪免疫细胞发育和功能的因素及其在我们建议检验我们的假设，即环境和治疗。 HSA 轴的基因激活通过脂肪细胞来源诱导脂肪驻留 NK 细胞白细胞介素15，可能对癌症有预防和治疗意义。表征 EE 诱导的脂肪 NK 细胞调节并阐明其机制目标 1. 具体而言，HSA 轴的作用将通过遗传（拮抗下丘脑 BDNF 信号传导）和药理学方法（β-肾上腺素能受体激动剂或拮抗剂）。评估脂肪细胞 IL-15 是否是关键的下游介质。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- 相关病毒载体可特异性地在脂肪细胞中过表达或敲低 IL-15。我们将研究EE诱导的脂肪NK细胞的预防和治疗作用 MMTV-PyMT 自发模型以及原位和转移性乳腺肿瘤目标 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，确定了一种新的脑-脂肪细胞-免疫轴，将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潜力的数据。

项目成果

期刊论文数量（36）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

A Protocol for Housing Mice in an Enriched Environment.

在丰富的环境中饲养小鼠的协议。

DOI：
发表时间：
2015-06-08
期刊：
影响因子：
0
作者：
Slater, Andrew M;Cao, Lei
通讯作者：
Cao, Lei

miRNA-32 Drives Brown Fat Thermogenesis and Trans-activates Subcutaneous White Fat Browning in Mice.

miRNA-32 驱动小鼠棕色脂肪产热并反式激活皮下白色脂肪褐变。

DOI：
发表时间：
2017-05-09
期刊：
影响因子：
8.8
作者：
Ng, Raymond;Hussain, Nurul Attiqah;Zhang, Qiongyi;Chang, Chengwei;Li, Hongyu;Fu, Yanyun;Cao, Lei;Han, Weiping;Stunkel, Walter;Xu, Feng
通讯作者：
Xu, Feng

Environmental Enrichment Mitigates Age-Related Metabolic Decline and Lewis Lung Carcinoma Growth in Aged Female Mice.

环境丰富可减轻老年雌性小鼠与年龄相关的代谢下降和刘易斯肺癌的生长。