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

描述（由申请人提供）：环境因素和生活方式对癌症的发生、促进和进展具有深远的影响。我们最近对环境富集（EE）的研究，一种促进心理健康的住房环境，揭示了一种新的表型，其特征在于肥胖症的稳健减少，对饮食诱导的肥胖的抵抗，更低的瘦素水平，更高的脂联素水平，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中提供的物理、社会和认知刺激刺激下丘脑中的脑源性神经营养因子（BDNF）表达，导致白色脂肪的优先交感神经激活。升高的交感神经驱动激活脂肪细胞β-肾上腺素能受体，抑制瘦素表达和释放，从而抑制癌症生长。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。具体来说，我们建议将HSA激活推广到其他癌症模型，特别是与肥胖相关性最强的癌症，如乳腺癌，并评估其长期预防作用。此外，我们计划确定是否通过BDNF基因治疗遗传激活HSA轴可以减轻肥胖和抑制黑皮质素受体4（MC 4 R）缺陷小鼠的肿瘤生长。此外，我们将评估是否长期BDNF基因治疗使用的自调节载体可以防止过早死亡的MC 4 R小鼠，模型代表最常见的单基因形式的肥胖。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，并提供临床前数据以评估最终临床干预的潜力 治疗癌症

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.