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）：癌症受个人与身体和社会环境的相互作用的影响，但基本机制的定义很差。流行病学研究表明，社会支持与癌症患者的健康结果的改善有关，而社会隔离预测了死亡率的风险。慢性应激模型中的机械研究表明，下丘脑 - 垂体 - 肾上腺（HPA）轴的激活延长，交感神经 - 肾上腺髓质（SAM）轴可能会促进癌症的进展。我们最近的工作表明，环境富集（EE）是一种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中提供的刺激刺激了下丘脑中脑衍生的神经营养因子（BDNF）的表达，从而导致白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，社会隔离（SI）与肿瘤负担增加有关。然而，EE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肾上腺素能阻止者可能会消除其对癌症的影响。这种明显的悖论可能部分在于缺乏对“ Eustress”（积极压力）和“困扰”（负压力）及其对立健康结果之间差异的认识。该项目的长期目标是了解如何触发和痛苦的事件如何触发大脑的明显分子变化，从而导致三个神经内分泌轴的策划差异激活：HPA，SAM和HSA，以及随后对癌症的相反影响。具体而言，我们建议使用多学科方法来提供有关癌症进展，代谢和脂肪生理学的EUSTESS模型与遇险模型之间的全面和明确的比较。对3轴的性质和幅度的分析将有助于阐明与Eustress相关的抗癌和与遇险相关的癌症表型的机制。此外，我们计划介绍激光捕获微解剖下丘脑核中的基因表达，以鉴定分子介质区分尤其是痛苦和困扰。此外，我们将研究下丘脑BDNF在介导SI对癌症影响的作用。这些研究可能揭示了用于预防癌症和治疗的新型治疗靶标。