Modulation of IGF-II Imprinting in the Aging Prostate

描述（由申请人提供）：前列腺癌的年龄依赖性和多灶性是前列腺癌的重要特征，将在本提案中解决。 IGF2 是细胞增殖的旁分泌和自分泌调节因子，在大多数正常成人组织中受到严格调节并保持严格的印记模式。基因组印记是一种表观遗传修饰，可导致基于亲本起源的基因差异表达（即仅来自一个等位基因）。在本次资助的上一个周期中，我们发现，在小鼠中，背外侧前列腺中发生了与衰老相关的器官特异性 IGF2 印记丧失，与 IGF2 水平升高相关。此外，这种表观遗传变化发生在患有前列腺癌的男性组织学正常的前列腺组织亚群中。目前的提案侧重于检验以下假设：与年龄相关的 IGF2 LOI 可以被调节，而且它会加速癌症的发展。我们的具体目标包括：i) 在易感小鼠中测试 IGF2 LOI 对前列腺癌发生的影响，ii) 确定诱导 CTCF 的干预措施是否维持 IGF2 印记，以及 iii) 定义并验证与人类前列腺癌发展相关的“场缺陷”中的 IGF2 LOI。该提议的新颖之处在于它提出了一种范例，其中基因组印记不是“固定的”，而是可以通过老化前列腺中的外部和内部因素进行调节。我们期望确定 IGF2 印记丢失是否可以预防以及其背后的测试机制。这项研究的基本原理是，通过定义前列腺中 IGF2 印记变化的病因和影响，将阐明改变这一过程发展的新治疗策略。这项研究的意义在于它有可能在体内衰老过程和前列腺癌发生之间提供关键的表观遗传联系。即使在不太可能发生的情况下，IGF2 在前列腺癌发生中只发挥很小的作用，这一提议代表了一种新颖且重要的方法来评估表观遗传领域的变化，这可能解释前列腺癌的年龄、器官和饮食相关的特异性。公共卫生相关性：为什么前列腺癌会随着年龄的增长而发生尚不清楚，但这种疾病对老龄化人口的影响是显着的，并且预计会增加。我们定义了一种新的表观遗传变化，即 IGF2 印记的丧失，这种变化会随着衰老而发生，并可识别患有这种疾病的男性。我们寻求进一步定义这一变化，以便开发预防癌症的新疗法，以及开发诊断前列腺癌和预测患该疾病的风险的新方法。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: Why prostate cancer develops with aging is unclear, yet the impact of this disease in the aging population is significant and expected to increase. We have defined a novel epigenetic change, the loss of IGF2 imprinting, that occurs with aging and identifies men who have developed the disease. We seek to further define this change in order to develop new therapies to prevent cancer, as well as develop new methods for diagnosing prostate cancer and predicting risk of developing the disease.