MODULATION OF IGF-II IMPRINTING IN THE AGING PROSTATE

老化前列腺中 IGF-II 印记的调节

• 批准号: 7077643
• 负责人: DAVID F. JARRARD
• 金额: $ 24.24万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-07-01 至 2008-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7077643
• 关键词: DNA methylation; aging; cancer risk; cell senescence; diet; dietary aminoacid; disease /disorder etiology; flow cytometry; gene environment interaction; gene expression; genetic susceptibility; genomic imprinting; human tissue; insulinlike growth factor; laboratory mouse; laser capture microdissection; male; methionine; neoplasm /cancer genetics; nutrition aspect of cancer; nutrition related tag; patient oriented research; prostate; prostate neoplasms; tissue /cell culture

Three important features of prostate cancer will be addressed in the present proposal that will improve our understanding of risk factors for the development of prostate cancer. These features include: i) the multifocality of prostate cancer which implicates a generalized or field change in cancer susceptibility, ii) the age-dependence of prostate cancer development, and iii) the important role of the Insulin-like Growth Factor Axis in both aging-related and genetic-related cancers. IGF-II is an auto-paracrine growth stimulator that is an important positive modulator of cancer development. We provide preliminary evidence that a loss of imprinting (LOI), or biallelic expression, is an age-related specific epigenetic alteration that occurs in the peripheral prostate of the human. The imprinting of IGF-II in adult tissues is typically maintained and LOI is a common attribute of prostate cancers. Since DNA methylation is a major determinant of IGF-II imprinting we would anticipate that changes in methylation would be associated with altered imprinting status. It is our hypothesis to be tested that a loss of genomic imprinting in IGF-II is an age-related event in prostate epithelial cells and may be modulated by changes in DNA methylation. In Specific Aim 1, we will determine if a LOI of IGF-II occurs in the aging mouse prostate. In Specific Aim 2, the impact of accelerating DNA methylation loss on imprinting in mouse and an in vitro human model will be assessed. Specific Aim 3 will determine whether these mechanisms, and/or others, engender the increase in IGF-II expression seen in aging. This proposal is significant and novel in that it has the ability to provide a critical epigenetic link between the aging process, diet and prostate carcinogenesis in vivo. We expect to determine whether IGF-II imprinting is altered with aging and whether altered DNA methylation is an underlying mechanism for this. Even in the unlikely event the IGF-II plays only a minor role in prostate carcinogenesis, this proposal represents a novel and important methodological approach to evaluating epigenetic field changes that may explain the age-, organ- and diet-related specificity of prostate cancer.

前列腺癌的三个重要特征将在本提案中得到解决，这将提高我们对前列腺癌发展风险因素的理解。 这些功能包括：i）前列腺癌的多灶性，其暗示癌症易感性的普遍或领域变化，ii）前列腺癌发展的年龄依赖性，和iii）胰岛素样生长因子轴在衰老相关和遗传相关癌症中的重要作用。 IGF-II是一种自动旁分泌生长刺激剂，是癌症发展的重要正调节剂。 我们提供的初步证据表明，印记（LOI），或双等位基因表达的损失，是一个年龄相关的特定的表观遗传学改变，发生在外周前列腺的人。IGF-II在成人组织中的印记通常被维持，并且LOI是前列腺癌的常见属性。 由于DNA甲基化是IGF-II印迹的主要决定因素，我们预期甲基化的变化与印迹状态的改变有关。 这是我们的假设进行测试，IGF-II基因组印记的损失是一个年龄相关的事件在前列腺上皮细胞，并可能通过DNA甲基化的变化进行调制。 在具体目标1中，我们将确定IGF-II的LOI是否发生在衰老小鼠前列腺中。 在特定目标2中，将评估DNA甲基化丢失加速对小鼠和体外人类模型中印迹的影响。 具体目标3将确定这些机制和/或其他机制是否会导致衰老中IGF-II表达的增加。 这一建议是重要的和新颖的，因为它有能力提供一个关键的表观遗传之间的联系老化过程，饮食和前列腺癌在体内。 我们希望确定IGF-II印迹是否随着衰老而改变，以及DNA甲基化改变是否是其潜在机制。 即使在不太可能的情况下，IGF-II在前列腺癌发生中仅起次要作用，该建议代表了一种新的和重要的方法来评估表观遗传领域的变化，可以解释前列腺癌的年龄，器官和饮食相关的特异性。