Transgenerational animal models of nutritional impact on cancer predisposition

营养对癌症易感性影响的跨代动物模型

• 批准号: 8072365
• 负责人: KELLE H MOLEY
• 金额: $ 22.65万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-06-15 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8072365
• 关键词: Adenocarcinoma; Adult; Age; Animal Model; Animals; Bioenergetics; Body Weight; Breast; Cells; Colorectal; Conceptions; Data; Development; Diet; Diethylstilbestrol; Disease; Endocrine; Energy Metabolism; Environmental Exposure; Epigenetic Process; Evaluation; Exposure to; Fatty acid glycerol esters; Gene Expression; Genes; H19 gene; Hematologic Neoplasms; Histologic; Hormonal; Hormone Responsive; Human; Human Development; Hyperplasia; Incidence; Knock-out; Lesion; Life; Link; Low Birth Weight Infant; Malignant Neoplasms; Malignant neoplasm of prostate; Mammary Neoplasms; Measurement; Messenger RNA; Metabolic; Modeling; Monitor; Mothers; Mus; Neonatal; Nutritional; Obesity; PTEN gene; Perinatal Exposure; Predisposition; Pregnancy; Premalignant; Prevention; Process; Prostate; Prostatic Intraepithelial Neoplasias; Recommendation; Rodent; Role; Severe dysplasia; Testing; Time; Tissues; Tumor-Associated Process; Western Blotting; Work; base; cell type; diet and cancer; disorder risk; energy balance; epigenomics; feeding; fetal; gland development; imprint; in utero; innovation; male; neoplastic; offspring; postnatal; prostate carcinogenesis; protein expression; pup; research study; stressor; tumor

The objective of the current study is to investigate the effect of maternal high fat diet and changes in metabolic bioenergetics on prostate gland development and susceptibility to prostate cancer in the male offspring. We hypothesize that a high fat maternal diet prior to and throughout pregnancy alters epigenomic marks leading to abnormal expression of key genes involved in the development of the prostate gland, which predispose the offspring to develop prostate cancer. Our rationale is that if maternal diet and metabolic bioenergetics alter the process of tumor development and progression in the prostate, then further studies exploring the mechanism of this process may elucidate new therapies and recommendations for the prevention and treatment of prostate cancer. To test our hypothesis the following aims will be pursued: Specific Aim 1: To examine prostate gland development and imprinted gene expression in control vs high fat fed offspring, from mothers given a high fat diet for 1 month prior to conception and throughout pregnancy.+ Specific Aim 2: To examine the incidence and timing of tumor development in offspring of control vs high fat fed mothers by administration of diethylstilbestrol (DES) to neonatal male mice on postnatal days 1-5. Specific Aim 3: To examine the effects of a high fat diet on tumor development in an established model for prostate cancers. The high fat diet experiment will be performed in mice with prostate specific knockout of PTEN vs controls (Pten[loxp/lop];PB-Cre4*) vs Pten*'*;PBCre4-). This proposal is innovative in that although data show that dietary changes during pregnancy can result in epigenetic changes in the offspring and that some of these epigenetic changes have been linked to prostate cancer, the connection between maternal diet and prostate cancer has never been explored. It is anticipated that the maternal diet of high fat will accelerate this process and decrease the latency period to the development of cancer. If successful in complefing our aims this work will advance our understanding of how changes in maternal diet and metabolic bioenergefics in utero have transgenerational effects on the predisposition and development of prostate cancer.

本研究旨在探讨母体高脂肪饮食和代谢生物能量学变化对雄性后代前列腺发育和前列腺癌易感性的影响。我们假设孕妇在怀孕前和怀孕期间的高脂肪饮食会改变表观基因组标记，导致参与前列腺发育的关键基因的异常表达，从而使后代易患前列腺癌。我们的理论基础是，如果母亲的饮食和代谢生物能量改变了前列腺肿瘤的发生和发展过程，那么进一步研究这一过程的机制可能会为前列腺癌的预防和治疗提供新的治疗方法和建议。为了验证我们的假设，将追求以下目标：具体目标1：检查前列腺