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: 8691755
• 负责人: Lei Cao
• 金额: $ 16.72万
• 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: 2013-07-01 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8691755
• 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）：肥胖症的全球流行和癌症的全球发病率都在上升。肥胖与某些类型癌症的风险增加有关，包括绝经后乳腺癌、肾癌、卵巢癌、食道癌、胰腺癌、前列腺癌、肝胆癌、结肠直肠癌和黑色素瘤。我们最近对环境富集（EE）的研究，一种促进心理健康的住房条件，揭示了一种新的表型，其特征在于肥胖症的稳健减少、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（DIO）的抵抗、更低的瘦素水平、更高的脂联素水平以及对黑色素瘤和结肠癌生长的显著抑制。一个关键的潜在机制是激活下丘脑-交感神经-脂肪细胞（HSA）轴，其中脑源性神经营养因子（BDNF）作为脑中的上游介质，瘦素作为介导抗癌表型的关键外周组分。这些数据支持脂肪重塑和癌症进展之间的联系。然而，肥胖并不总是与胰岛素抵抗或不良代谢谱有关。人们对脂肪组织的健康扩张在改善胰岛素敏感性中的作用非常感兴趣。人腺病毒36型（Ad-36）可以作为一种新的模型分离脂肪膨胀的常见不良健康后果的肥胖症，包括糖尿病和癌症。Ad-36分别与动物和人类的肥胖症有因果关系和相关性。然而，Ad-36感染矛盾地改善血糖控制，增加脂联素水平，并降低瘦素水平。这些特征与HSA轴激活诱导的抗癌表型密切相关，尽管HSA轴激活导致消瘦。该项目的目标是研究脂肪组织的健康扩张对癌症生长的影响。具体地说，我们建议使用脂肪形成Ad-36作为肥胖症的一个子集的模型，该肥胖症源自脂肪组织的代谢有利的重塑并且是胰岛素敏感的。 我们计划在正常体重动物和常规DIO模型中全面表征Ad-36感染对脂肪重塑、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理解肥胖在癌症进展中的作用，阐明改变的脂肪因子谱（特别是脂联素/瘦素比率）与脂肪组织本身的扩张对癌症风险的贡献，并刺激研究利用微生物的某些特性以达到有益的目的。