Cancer Prevention and Treatment by Activation of a Brain-Adipocyte Axis

描述（申请人提供）：环境因素和生活方式对癌症的发生、促进和发展有着深远的影响。我们最近对环境富集（EE）的研究，一种促进心理健康的居住环境，揭示了一种新的表型，其特征是肥胖的显著减少，对饮食引起的肥胖的抵抗，较低的瘦素水平，较高的脂联素水平，增强的免疫功能，以及对黑色素瘤和结肠癌生长的显著抑制。一个关键的潜在机制是下丘脑-交感神经-脂肪细胞（HSA）轴的激活，由此，EE提供的身体、社会和认知刺激刺激下丘脑的脑源性神经营养因子（BDNF）表达，导致白色脂肪优先交感神经激活。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轴在癌症发生和进展中的作用。具体而言，我们建议将HSA激活推广到其他癌症模型，特别是与肥胖密切相关的癌症，如乳腺癌，并评估其长期预防效果。此外，我们计划确定通过BDNF基因治疗基因激活HSA轴是否可以减轻黑素皮质素受体4 （MC4R）缺陷小鼠的肥胖和抑制肿瘤生长。此外，我们将评估使用自调节载体的长期BDNF基因治疗是否可以预防MC4R小鼠的过早死亡，MC4R小鼠是最常见的单基因肥胖模型。这些研究将进一步表征HSA轴，阐明潜在的机制，确定潜在的治疗靶点，并提供临床前数据来评估最终临床干预的潜力

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.