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.

项目摘要环境因素和生活方式对倡议，促进和癌症的进展。我们关于环境丰富的工作（EE），住房环境提高心理健康，揭示了一种新颖的表型，其特征是减少肥胖，对饮食诱发的肥胖症的抗性，较低的瘦素水平，脂肪素水平较高，增强免疫功能，并在黑色素瘤，乳腺癌和结肠癌中明显抑制生长。从机械上讲，EE中提供的身体，社会和认知刺激刺激下丘脑脑衍生的神经营养因子（BDNF）表达，从而激活A 特定的神经内分泌轴，下丘脑 - 同情辅助细胞（HSA）轴，导致抑制瘦素表达和释放，以及白脂肪褐变。 EE还增强了t 通过交感神经系统（SNS）和下丘脑 - 垂体 - 肾上腺（HPA）轴。代谢和免疫调节都有助于抗抗菌 EE的效果，由下丘脑BDNF精心策划。此外，我们的初步数据表明，EE影响脂肪居住的天然杀手（NK）细胞也可能由 HSA轴。该项目的长期目标是研究生活方式和环境因素调节脂肪免疫细胞的发育和功能及其在预防癌症和治疗。我们建议检验我们的假设，即环境和 HSA轴的遗传激活通过脂肪细胞来诱导脂肪居民NK细胞白介素15，可能具有癌症的预防和治疗意义。我们计划表征EE诱导的脂肪NK细胞的调节，并阐明目标1.特别是，将通过遗传（拮抗）研究HSA轴的作用下丘脑BDNF信号传导）和药物方法（β-肾上腺素能受体激动剂或对手）。评估脂肪细胞IL-15是否是下游介体的关键。拟议的脑脂肪细胞-NK轴，我们将使用我们的新型脂肪特异性重组腺相关的病毒载体过表达或敲除脂肪细胞中的IL-15。而且，我们将研究EE诱导的脂肪NK细胞对 MMTV-PYMT自发模型以及原位和转移性的乳腺肿瘤 AIM 2中乳腺癌的移植模型。这些研究将进一步表征脑介导的抗癌作用，确定一个新型的脑脂肪细胞免疫轴，将对身体和社会环境的有益自适应反应，并提供临床前数据以评估最终临床干预的潜力。

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）

Induction of adipose and hepatic SWELL1 expression is required for maintaining systemic insulin-sensitivity in obesity.

诱导脂肪和肝脏 SWELL1 表达是维持肥胖患者全身胰岛素敏感性所必需的。

DOI：
10.1080/19336950.2017.1373225
发表时间：
2017
期刊：
Channels (Austin, Tex.)
影响因子：
0
作者：
Xie,Litao;Zhang,Yanhui;Gunasekar,SusheelK;Mishra,Anil;Cao,Lei;Sah,Rajan
通讯作者：
Sah,Rajan

Visceral adipose tissue-directed FGF21 gene therapy improves metabolic and immune health in BTBR mice.

DOI：
10.1016/j.omtm.2020.12.011
发表时间：
2021-03-12
期刊：
Molecular therapy. Methods & clinical development
影响因子：
0
作者：
Queen NJ;Bates R;Huang W;Xiao R;Appana B;Cao L
通讯作者：
Cao L

LMO3 reprograms visceral adipocyte metabolism during obesity.

DOI：
10.1007/s00109-021-02089-9
发表时间：
2021-08
期刊：
Journal of molecular medicine (Berlin, Germany)
影响因子：
0
作者：
Wagner G;Fenzl A;Lindroos-Christensen J;Einwallner E;Husa J;Witzeneder N;Rauscher S;Gröger M;Derdak S;Mohr T;Sutterlüty H;Klinglmüller F;Wolkerstorfer S;Fondi M;Hoermann G;Cao L;Wagner O;Kiefer FW;Esterbauer H;Bilban M
通讯作者：
Bilban M

Regulation of aging and cancer by enhanced environmental activation of a hypothalamic-sympathoneural-adipocyte axis.