Modulating cancer progression by adipogenic human adenovirus type 36

36 型脂肪人腺病毒调节癌症进展

• 批准号: 8567581
• 负责人: Lei Cao
• 金额: $ 20.79万
• 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: 2013-07-01 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8567581
• 关键词: Accounting; Adenovirus Infections; Adenoviruses; Adipocytes; Adipose tissue; Adult; Animals; Attenuated; Biological Markers; Body Weight decreased; Brain; Brain-Derived Neurotrophic Factor; Breast; Brown Fat; Cells; Cessation of life; Characteristics; Child; Cognitive; Colon Carcinoma; Colorectal; Cross-Sectional Studies; Data; Diabetes Mellitus; Diet; Drops; Energy Metabolism; Epidemic; Esophagus; Fatty acid glycerol esters; Gene Expression; Gene Expression Profile; Genetic; Genetic Models; Goals; Growth; Health; Hepatobiliary; Housing; Human; Human Adenoviruses; Hypothalamic structure; Implant; Incidence; Infection; Insulin; Insulin Resistance; Insulin-Like Growth Factor I; Intestinal Cancer; Kidney; Leptin; Link; Longitudinal Studies; MC38; Malignant Neoplasms; Measures; Mediating; Mediator of activation protein; Mental Health; Metabolic; Metabolic syndrome; Metabolism; Microbe; Modeling; Monitor; Mus; Obesity; Obesity associated cancer; Operative Surgical Procedures; Ovarian; Pancreas; Peripheral; Phenotype; Ploidies; Postmenopause; Property; Prostate; Research; Resistance; Risk; Role; Stimulus; Testing; Thinness; Time; Transplantation; Tumor Volume; Virus; Weight; Woman; adiponectin; base; cancer cell; cancer risk; cancer type; environmental enrichment for laboratory animals; feeding; glucose tolerance; glycemic control; implantation; improved; insulin sensitivity; insulin sensitivity/resistance; interest; melanoma; men; mortality; neoplastic cell; novel; prevent; public health relevance; social; tumor; tumor growth; tumor metabolism; tumor progression; viral DNA

DESCRIPTION (provided by applicant): The worldwide epidemic of obesity and global incidence of cancer are both rising. Obesity is linked to an increased risk of certain types of cancer including postmenopausal breast, renal, ovarian, esophagus, pancreas, prostate, hepatobiliary, colorectal, and melanoma. Our recent research on environmental enrichment (EE), a housing condition boosting mental health, has revealed a novel phenotype characterized by a robust reduction in adiposity, white to brown adipocyte phenotypic switch, enhanced insulin sensitivity, resistance to diet-induced obesity (DIO), lower leptin level, higher adiponectin level and marked inhibition in melanoma and colon cancer growth. One key underlying mechanism is the activation of the hypothalamic- sympathoneural-adipocyte (HSA) axis with brain-derived neurotrophic factor (BDNF) as the upstream mediator in the brain and leptin as the key peripheral component mediating the anticancer phenotype. These data support the link between adipose remodeling and cancer progression. However obesity is not always linked to insulin resistance or adverse metabolic profile. There is considerable interest in the role of the healthy expansion of adipose tissue in improving insulin sensitivity. Human adenovirus type 36 (Ad-36) can serve as a novel model dissociating adipose expansion from the common adverse health consequences of obesity including diabetes and cancer. Ad-36 has been causatively and correlatively linked with obesity in animals and humans, respectively. However Ad-36 infection paradoxically improves glycemic control, increases adiponectin level, and decreases leptin level. These are the features resemble those closely related to the anticancer phenotype induced by the activation of the HSA axis, although HSA axis activation causes leanness. The goal of this project is to study the effects of healthy expansion of adipose tissue on cancer growth. Specifically we propose to use the adipogenic Ad-36 as a model of a subset of obesity that is derived from metabolically favorable remodeling of adipose tissue and is insulin sensitive. We plan to comprehensively characterize the effects of Ad-36 infection on adipose remodeling, metabolism, hypothalamic gene expression, and cancer progression in both normal weight animals and conventional DIO model. Accomplishing the proposed studies may help to better understand the role of adiposity in cancer progression, clarify the contribution of altered adipokine profiles (specifically the adiponectin/leptin ratio) versus expansion of adipose tissue per se to cancer risk, and stimulate studies to harness certain properties of microbes for beneficial purposes.

描述（由申请人提供）：肥胖和癌症全球发病率的全球流行都在上升。肥胖与某些类型癌症的风险增加有关，包括绝经后乳房，肾脏，卵巢，食道，胰腺，前列腺，前列腺胆质，结直肠癌和黑色素瘤。我们最近在环境丰富方面的研究（EE）是一种增强心理健康状况的住房状况，它揭示了一种新型表型，其特征是脂肪的稳健降低，白色至棕色脂肪细胞表型转换，胰岛素敏感性增强，对饮食诱导的肥胖症（DIO）的耐药性（DIO）的耐药性（DIO），脂肪素水平较低，脂肪素水平较高，并在癌症中降低了癌症和明显的水平。一个关键的潜在机制是，与脑衍生的神经营养因子（BDNF）作为大脑中的上游介体作为介导抗癌现象的关键外周成分，将下丘脑 - 淋手辅助 - 辅助细胞（HSA）轴激活。这些数据支持脂肪重塑与癌症进展之间的联系。但是，肥胖并不总是与胰岛素抵抗或不良代谢谱有关。脂肪组织在改善胰岛素敏感性方面的健康扩张的作用引起了很大的兴趣。人类腺病毒36型（AD-36）可以用作一种新型模型，将脂肪扩张与包括糖尿病和癌症在内的肥胖症的常见不良健康后果相比。 AD-36分别与动物和人类的肥胖症有关。但是，AD-36感染矛盾地改善了血糖控制，增加脂联素水平并降低瘦素水平。这些特征类似于与HSA轴激活引起的抗癌表型密切相关的特征，尽管HSA轴激活会导致倾斜度。该项目的目的是研究脂肪组织健康扩张对癌症生长的影响。具体而言，我们建议将脂肪生成AD-36用作肥胖子集的模型，该模型是从代谢上有利的脂肪组织重塑而得出的，并且对胰岛素敏感。 我们计划全面地表征AD-36感染对正常体重动物和常规DIO模型中脂肪重塑，代谢，下丘脑基因表达和癌症进展的影响。完成拟议的研究可能有助于更好地了解脂肪在癌症进展中的作用，阐明脂肪因子变化的贡献（特别是脂联素/瘦素比）与脂肪组织的扩展本身对癌症风险的扩展，并刺激研究对有利于有益目的的某些特性来利用微生物的某些特性。