Identifying brain mediators distinguishing eustress and distress impact on cancer

描述（由申请人提供）：癌症受到个体与其物理和社会环境相互作用的影响，但其潜在机制尚不明确。流行病学研究表明，社会支持与癌症患者健康状况的改善有关，而社会孤立则预示着死亡风险。慢性应激模型的机制研究表明，下丘脑-垂体-肾上腺（HPA）轴和交感-肾上腺髓质（SAM）轴的长期激活可能促进癌症的进展。我们最近的工作表明，环境富集（EE），一个促进心理健康的住房环境，通过激活下丘脑-交感神经-脂肪细胞（HSA）轴来抑制肿瘤的生长。EE提供的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。相反，社会孤立（SI）与肿瘤负担增加有关。然而，情感表达和SI都会增加经典的应激激素、糖皮质激素和儿茶酚胺，而ß -肾上腺素能阻滞剂可能会消除它们对癌症的影响。这种明显的矛盾可能部分在于缺乏对“正面压力”（eustress）和“负面压力”（distress）之间的区别以及它们相反的健康结果的认识。该项目的长期目标是了解压力和痛苦事件如何触发大脑中不同的分子变化，从而导致三种神经内分泌轴（HPA， SAM和HSA）的精心安排的差异激活，以及随后对癌症的相反影响。具体来说，我们建议采用多学科方法，对应激模型EE和应激模型SI在癌症进展、代谢和脂肪生理方面进行全面而明确的比较。对这3个轴的性质和大小的分析将有助于阐明压力相关的抗癌与痛苦相关的癌前表型的机制。此外，我们计划在激光捕获微解剖下丘脑核中分析基因表达，以识别区分应激和应激的分子介质。此外，我们将研究下丘脑BDNF在SI对癌症的影响中的作用。这些研究可能为癌症的预防和治疗揭示新的治疗靶点。

DESCRIPTION (provided by applicant): Cancer is influenced by an individual's interaction with its physical and social environment, yet the underlying mechanisms are poorly defined. Epidemiological studies have revealed that social support is linked to improved health outcomes among cancer patients whereas social isolation predicts risk for mortality. Mechanistic studies in chronic stress models suggest that prolonged activation of the hypothalamic-pituitary-adrenal (HPA) axis and the sympathetic-adrenal medullary (SAM) axis may promote cancer progression. Our recent work has shown that environmental enrichment (EE), a housing environment boosting mental health, inhibits tumor growth by activating the hypothalamic- sympathoneural-adipocyte (HSA) axis. The 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. In contrast, social isolation (SI) is linked to increased tumor burden. However, both EE and SI increase the classical stress hormones, glucocorticoids and catecholamines, and ss-adrenergic blockers may abrogate their effects on cancer. This apparent paradox may in part lie in the lack of recognition of the difference between "eustress" (positive stress) and "distress" (negative stress) and their opposing health outcomes. The long-term goal of this project is to understand how the eustressful and distressful events trigger distinct molecular changes in the brain leading to an orchestrated differential activation of the three neuroendocrine axes: HPA, SAM and HSA, and subsequent opposite influences on cancer. Specifically we propose to use a multidisciplinary approach to provide a comprehensive and explicit comparison between the eustress model EE versus distress model SI on cancer progression, metabolism, and fat physiology. The analysis of the nature and magnitude of the 3 axes will help to elucidate the mechanisms underlying eustress-associated anticancer versus distress-associated pro- cancer phenotype. In addition we plan to profile the gene expression in the laser-capture microdissected hypothalamus nuclei to identify molecular mediators distinguishing eustress and distress. Furthermore we will investigate the role of hypothalamic BDNF in mediating SI impact on cancer. These studies may reveal novel therapeutic targets for cancer prevention and treatment.