Modulation Of IGF-II Imprinting in the Aging Prostate

前列腺癌的年龄依赖性和多灶性是前列腺癌的重要特征， 癌症将在本提案中得到解决。IGF2是一种旁分泌和自分泌的细胞调节因子 在大多数正常成人组织中，增殖受到严格调控并保持严格的印记模式。 基因组印记是一种表观遗传修饰，其导致差异表达（即仅来自 一个等位基因）。在上一轮拨款中，我们发现， 在小鼠的背外侧前列腺中发生了与衰老相关的、器官特异性的IGF2印迹丢失 与IGF2水平升高有关。此外，这种表观遗传变化发生在 组织学上正常的前列腺组织，来自患有相关前列腺癌的男性。当前 这项提案的重点是检验与年龄相关的IGF2 LOI可以被调节的假设， 此外，它会加速癌症的发展。我们的具体目标包括：i）测试 IGF2 LOI对易感小鼠前列腺癌发生的影响，ii）确定是否 诱导CTCF的干预维持IGF2印记，和iii）在CTCF中定义和验证IGF2 LOI。 与人类前列腺癌发展相关的磁场缺陷。 这一提议是新颖的，因为它提出了一个范式，其中基因组印记是不固定的。 但可由老化前列腺中的外部和内部因素调节。我们希望能确定 IGF2印迹损失是否可以防止和测试机制的基础。的理由 通过定义IGF2印迹的病因和影响， 前列腺的变化，新的治疗策略，改变这一进程的发展将是 阐明。这项研究意义重大，因为它有可能提供一个关键的表观遗传联系 在体内老化过程和前列腺癌发生之间的联系。即使在不太可能的情况下，IGF2 在前列腺癌的发生中只起很小的作用，这个提议代表了一个新的和重要的 评价表观遗传领域变化的方法学方法，可以解释年龄，器官和 饮食相关的前列腺癌特异性。

The age-dependence and multifocality of prostate cancer are important features of prostate cancer that will be addressed in the present proposal. IGF2, a paracrine and autocrine regulator of cell proliferation, is tightly regulated and maintains a strict imprinted pattern in most normal adult tissues. Genomic imprinting is an epigenetic modification that leads to the differential expression (i.e. only from one allele) of a gene based on parental origin. In the previous cycle of this grant, we found that in the mouse an aging-related, organ-specific loss of imprinting at IGF2 occurs in the dorsolateral prostate associated with increased IGF2 levels. Furthermore, this epigenetic change develops in that subset of histologically normal prostate tissues from men that have associated prostate cancer. The current proposal focuses on testing the hypothesis that age-related IGF2 LOI can be modulated and furthermore, that it accelerates the development of cancer. Our Specific Aims include: i) testing the impact of IGF2 LOI on prostate carcinogenesis in a susceptible mouse, ii) determining whether interventions that induce CTCF maintain IGF2 imprinting, and iii) define and validate IGF2 LOI in the ¿field defect¿ associated with human prostate cancer development. This proposal is novel in that it proposes a paradigm in which genomic imprinting is not ¿fixed¿ but may be modulated by external and internal factors in the aging prostate. We expect to determine whether IGF2 imprinting loss can be prevented and the test mechanisms underlying this. The rationale that underlies the proposed research is that by defining the etiology and impact of IGF2 imprinting changes in the prostate, new therapeutic strategies for altering the development of this process will be elucidated. This study is significant in that it has the potential to provide a critical epigenetic link between the aging process and prostate carcinogenesis in vivo. Even in the unlikely event the IGF2 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.