Identifying brain mediators distinguishing eustress and distress impact on cancer

描述(申请人提供)：癌症受个体与其物理和社会环境的相互作用的影响，但其潜在的机制尚不清楚。流行病学研究表明，社会支持与改善癌症患者的健康状况有关，而社会隔离则预示着死亡风险。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-肾上腺髓质轴(SAM)的长期激活可能促进癌症的进展。我们最近的工作表明，环境丰富(EE)，一个促进精神健康的住房环境，通过激活下丘脑-交感神经-脂肪细胞(HSA)轴来抑制肿瘤生长。EE提供的刺激刺激脑源性神经营养因子(BDNF)在下丘脑中的表达，导致白色脂肪的优先交感神经激活。交感神经驱动的升高激活脂肪细胞的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。相比之下，社会隔离(SI)与增加肿瘤负担有关。然而，EE和SI都增加了经典的应激激素、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人们没有认识到“正压力”(积极压力)和“痛苦”(消极压力)之间的区别以及它们相反的健康后果。该项目的长期目标是了解正常应激和痛苦事件如何触发大脑中不同的分子变化，导致三个神经内分泌轴：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。具体地说，我们建议使用多学科方法，在癌症进展、新陈代谢和脂肪生理学方面提供正常应激模型EE和痛苦模型SI之间的全面和明确的比较。对三个轴的性质和大小的分析将有助于阐明与正应激相关的抗癌和与窘迫相关的癌前表型之间的机制。此外，我们计划对激光捕获显微解剖的下丘脑核团中的基因表达进行分析，以确定区分正应激和窘迫的分子介质。此外，我们还将研究下丘脑BDNF在SI对癌症的影响中的作用。这些研究可能揭示癌症预防和治疗的新治疗靶点。

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.