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：
8439638
负责人：
Lei Cao
金额：
$ 31.75万
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 2017-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8439638
关键词：
Adipocytes Adipose tissue Adrenergic Receptor Animals Body Composition Brain Brain-Derived Neurotrophic Factor Breast Cancer Model Cancer Intervention Cancer Model Cancer Patient Cancer Prevention Intervention Clinical Cognitive Colon Carcinoma Data Development Diet Environment Environmental Risk Factor Epidemiologic Studies Exercise Fatty acid glycerol esters Gene Transfer Genetic Goals Growth Health Hormone Responsive Housing Hypothalamic structure Individual Insulin-Like Growth Factor I Intervention Knowledge Leptin Life Life Style Link Long-Term Effects Longevity Malignant Neoplasms Mammary Neoplasms Mammary Tumorigenesis Mediating Melanocortin 4 Receptor Mental Health Metabolism Modeling Mouse Mammary Tumor Virus Mus Obesity Outcome Phenotype Physical environment Premature Mortality Preventive Psychological Stress Recombinants Resistance Risk Role Serum Social Environment Social isolation Social support Testing Therapeutic Therapeutic Effect Transgenic Mice Well in self Work adeno-associated viral vector adiponectin cancer prevention cancer therapy environmental enrichment for laboratory animals gene therapy immune function improved insulin sensitivity malignant breast neoplasm melanoma mortality novel pre-clinical prevent prospective public health relevance social therapeutic target tumor growth tumor progression vector

项目摘要

DESCRIPTION (provided by applicant): Environmental factors and lifestyle have profound effects in the initiation, promotion and progression of cancer. Our recent 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 and colon cancer growth. One key underlying mechanism is the activation of the hypothalamic- sympathoneural-adipocyte (HSA) axis whereby the physical, social and cognitive stimulations provided in EE stimulate brain-derived neurotrophic factor (BDNF) expression in the hypothalamus leading to preferential sympathoneural activation of white fat. The elevated sympathetic drive activates adipocyte ss-adrenergic receptors inhibiting leptin expression and release, and thereby suppresses cancer growth. The long-term goal of this project is to further characterize the role of HSA axis in cancer development and progression. Specifically we propose to generalize HSA activation to additional cancer models particularly the cancers with the strongest association with obesity such as breast cancer, and evaluate its long-term preventive effects. In addition we plan to determine whether genetically activating HSA axis by BDNF gene therapy can alleviate obesity and inhibit tumor growth in melanocortin receptor 4 (MC4R) deficient mice. Moreover we will evaluate whether long-term BDNF gene therapy using an autoregulatory vector can prevent the premature mortality in MC4R mice, a model representing the most common monogenic form of obesity. These studies will further characterize the HSA axis, elucidate underlying mechanisms, identify potential therapeutic targets, and provide the preclinical data to assess the potential to ultimate clinical intervention for cancer.

描述（由申请人提供）：环境因素和生活方式对癌症的启动，促进和发展具有深远的影响。我们最近在环境丰富方面的工作（EE）是一种促进心理健康的住房环境，揭示了一种新型的表型，其特征是肥胖，对饮食诱导的肥胖症的抗性，较低的瘦素水平，较高的脂联蛋白水平，较高的脂联素水平，增强的免疫功能以及明显的抑制黑素瘤和结肠癌的抑制作用。一个关键的潜在机制是下丘脑性交感神经 - 脂肪细胞（HSA）轴的激活，在下丘脑中，EE中提供的物理，社会和认知刺激刺激了脑衍生的神经营养因子（BDNF）表达，导致下丘脑带来对白色脂肪造成的优先交感神经活化。升高的交感神经驱动激活脂肪细胞SS-肾上腺素能受体抑制瘦素的表达和释放，从而抑制癌症的生长。该项目的长期目标是进一步表征HSA轴在癌症发展和进展中的作用。具体而言，我们建议将HSA激活推广到其他癌症模型，尤其是与肥胖症（如乳腺癌）最强的癌症，并评估其长期预防作用。此外，我们计划确定BDNF基因疗法通过遗传激活HSA轴是否可以减轻肥胖症并抑制黑色素皮质受体4（MC4R）缺陷小鼠的肿瘤生长。此外，我们将评估使用自动调节载体的长期BDNF基因治疗是否可以防止MC4R小鼠的过早死亡率，这是代表最常见的单基因肥胖形式的模型。这些研究将进一步表征HSA轴，阐明基本机制，确定潜在的治疗靶标，并提供临床前数据，以评估最终的临床干预的潜力用于癌症。