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，将在本提案中讨论。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控并保持严格的印迹模式。基因组印记是一种表观遗传修饰，导致基于亲代起源的基因的差异表达（即仅来自一个等位基因）。在本研究的前一个周期中，我们发现在小鼠中，与IGF2水平升高相关的前列腺背外侧IGF2印迹的衰老相关的器官特异性丢失。此外，这种表观遗传变化发生在患有相关前列腺癌的男性的组织学正常前列腺组织亚群中。目前的建议侧重于测试与年龄相关的IGF2 LOI可以被调节的假设，进一步说，它加速了癌症的发展。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的干预是否维持IGF2印记，以及iii)定义和验证IGF2 LOI在与人类前列腺癌发展相关的“场缺陷”中。这一建议是新颖的，因为它提出了一种范式，在这种范式中，基因组印记不是“固定的”，而是可能由衰老的前列腺的外部和内部因素调节。我们期望确定是否可以防止IGF2印迹丢失及其潜在的测试机制。这项研究的基本原理是，通过确定前列腺中IGF2印迹变化的病因和影响，将阐明改变这一过程发展的新治疗策略。这项研究具有重要意义，因为它有可能在体内提供衰老过程和前列腺癌发生之间的关键表观遗传联系。即使IGF2在前列腺癌的发生过程中只起很小的作用，这一建议也代表了一种新的重要的方法来评估表观遗传场的变化，这种变化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增长而发展尚不清楚，但这种疾病在老龄化人口中的影响是显著的，并且预计会增加。我们已经定义了一种新的表观遗传变化，即IGF2印记的丢失，这种变化随着年龄的增长而发生，并识别出患有这种疾病的男性。我们试图进一步定义这种变化，以便开发新的治疗方法来预防癌症，以及开发诊断前列腺癌和预测患病风险的新方法。

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.