Transgenerational animal models of nutritional impact on cancer predisposition

本研究的目的是探讨母体高脂饮食和代谢生物能量学变化对雄性子代前列腺癌易感性和前列腺发育的影响。我们假设，怀孕前和怀孕期间高脂肪的母亲饮食会改变表观基因组标记，导致与前列腺发育有关的关键基因的异常表达，从而使后代容易患前列腺癌。我们的理论基础是，如果母亲的饮食和代谢生物能量学改变了前列腺癌的发生和发展过程，那么进一步探索这一过程的机制可能会阐明预防和治疗前列腺癌的新疗法和建议。为了验证我们的假设，我们将追求以下目标：具体目标1：检查前列腺癌 在对照组和高脂肪喂养的后代中，母亲在怀孕前1个月和整个怀孕期间给予高脂肪饮食，研究对象的发育和印记基因表达。 具体目的2：通过给出生后1-5天的新生雄性小鼠注射己烯雌酚(DES)，观察对照组和高脂喂养母亲的子代肿瘤的发生率和发生的时间。具体目标3：检查高脂肪饮食的效果 关于前列腺癌已建立的模型中的肿瘤发展。高脂饮食实验将在前列腺特异性PTEN基因敲除的小鼠和对照组(Pten[loxP/lop]；PB-Cre4*)VS Pten*‘*；PBCre4-)中进行。 这一建议的创新之处在于，尽管有数据表明，怀孕期间饮食的变化可以 导致后代的表观遗传变化，其中一些表观遗传变化与 前列腺癌，母亲的饮食和前列腺癌之间的联系从未被探索过。它是 预计高脂肪的母亲饮食将加速这一过程，并缩短到 癌症的发展。如果成功地完成了我们的目标，这项工作将促进我们对 母亲饮食和宫内代谢生物能量的变化对婴儿的代谢性影响 前列腺癌的易感性和发展。

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.