Identifying brain mediators distinguishing eustress and distress impact on cancer

识别区分良性压力和痛苦对癌症影响的大脑调节因子

• 批准号: 8641669
• 负责人: Lei Cao
• 金额: $ 22.72万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-04-01 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8641669
• 关键词: Adipocytes; Adrenal Glands; Adrenergic Antagonists; Adrenergic Receptor; Animals; Anxiety; Brain; Brain region; Brain-Derived Neurotrophic Factor; Cancer Patient; Catecholamines; Cell Nucleus; Chronic stress; Cognitive; Data; Development; Distress; Down-Regulation; Drops; Environment; Epidemiologic Studies; Event; Fatty acid glycerol esters; Gene Expression; Gene Expression Profile; Gene Transfer; Genes; Glucocorticoids; Goals; Growth; Health; Hormones; Housing; Hypothalamic structure; Individual; Lasers; Leptin; Link; Malignant Neoplasms; Mediating; Mediator of activation protein; Mental Health; Metabolism; Modeling; Molecular; Molecular Profiling; Mus; Nature; Neurosecretory Systems; Obesity; Outcome; Pathway interactions; Pattern; Phenotype; Physical environment; Physiology; Pituitary Gland; Psychological Stress; Regulation; Reporting; Risk; Role; Social Environment; Social isolation; Social support; Stress; Structure of nucleus infundibularis hypothalami; System; Testing; Tumor Burden; Up-Regulation; Well in self; Work; biological adaptation to stress; cancer prevention; cancer therapy; environmental enrichment for laboratory animals; hypothalamic-pituitary-adrenal axis; improved; interdisciplinary approach; lipid metabolism; melanoma; mortality; new therapeutic target; physical conditioning; prevent; prospective; public health relevance; relating to nervous system; social; tumor growth; tumor progression

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.

描述（由申请人提供）：癌症受个体与其物理和社会环境相互作用的影响，但其潜在机制尚不清楚。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）轴和交感神经-肾上腺髓质（SAM）轴的长期激活可能会促进癌症进展。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）轴抑制肿瘤生长。EE中提供的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。相反，社会隔离（SI）与肿瘤负荷增加有关。然而，EE和SI增加经典的应激激素，糖皮质激素和儿茶酚胺，β-肾上腺素能受体阻滞剂可能会消除其对癌症的影响。这种明显的矛盾可能部分在于缺乏对“积极压力”（积极压力）和“痛苦”（消极压力）之间的区别及其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，导致三个神经内分泌轴的协调差异激活：HPA，SAM和HSA，以及随后对癌症的相反影响。具体来说，我们建议使用多学科的方法，提供一个全面和明确的比较之间的良性应激模型EE与痛苦模型SI癌症进展，代谢和脂肪生理。对3个轴的性质和大小的分析将有助于阐明良性应激相关的抗癌与痛苦相关的促癌表型的潜在机制。此外，我们计划在激光捕获显微切割下丘脑核的基因表达谱，以确定区分正常应激和痛苦的分子介质。此外，我们将研究下丘脑BDNF在介导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。