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: 7656965
• 负责人: DAVID F. JARRARD
• 金额: $ 24.97万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-01 至 2009-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7656965
• 关键词: Address; Adult; Age; Aging; Aging-Related Process; Alleles; Binding; Caloric Restriction; Cancerous; Cause of Death; Cell Proliferation; Cell model; Cells; DNA Methylation; Dependence; Development; Diet; Dietary Intervention; Disease; Disease Progression; Down-Regulation; Enhancers; Epigenetic Process; Epithelial Cells; Etiology; Event; Funding; Genes; Genomic Imprinting; Goals; Grant; H19 gene; Histologic; Human; IGF2 gene; Insulin-Like Growth Factor II; Intervention; Link; Lobe; Malignant Neoplasms; Malignant neoplasm of prostate; Mammals; Mediating; Methylation; Microdissection; Minor; Modification; Molecular; Mus; NKX3-1 gene; Organ; Oxidative Stress; Pathway interactions; Pattern; Peripheral; Play; Population; Positioning Attribute; Predisposition; Process; Prostate; Prostatic Neoplasms; Protein Overexpression; Proteins; Regulation; Repression; Research; Research Personnel; Resveratrol; Role; Signal Transduction; Site; Specificity; Testing; Tissues; Tumor Suppressor Genes; age related; autocrine; base; cancer diagnosis; carcinogenesis; human tissue; imprint; in vivo; male; men; mouse model; novel; novel therapeutics; paracrine; prevent; promoter; senescence; tumor

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.

前列腺癌的年龄依赖性和多灶性是前列腺癌的重要特征。 将在本提案中解决的癌症问题。细胞旁分泌和自分泌调节因子IGF2 增殖，受到严格调控，并在大多数正常成人组织中保持严格的印迹模式。 基因组印记是一种表观遗传修饰，它导致差异表达(即仅来自 基于亲本来源的基因的一个等位基因。在这笔赠款的前一个周期中，我们发现在 小鼠前列腺背外侧发生与衰老相关的器官特异性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这一子集 来自与前列腺癌相关的男性的正常前列腺组织。海流 该提案的重点是检验年龄相关的IGF2 LOI可以被调节和 此外，它还会加速癌症的发展。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 诱导CTCF的干预措施维持IGF2印记，以及iii)定义和验证IGF2 LOI在 “视野缺陷”与人类前列腺癌的发展有关。 这一建议是新颖的，因为它提出了一种基因组印记不是固定的范式 但在老化的前列腺中可能受到外部和内部因素的调节。我们预计将确定 是否可以防止IGF2印迹丢失以及其背后的测试机制。其基本原理是 这项拟议的研究的基础是，通过定义IGF2印记的病因和影响 前列腺的变化，新的治疗策略将改变这一过程的发展 已澄清。这项研究具有重要意义，因为它有可能提供关键的表观遗传学联系 在体内衰老过程和前列腺癌发生之间的关系。即使在不太可能的情况下，IGF2 在前列腺癌的发生中只起到很小的作用，这一建议代表了一种新的和重要的 评估表观遗传场变化的方法学途径，可解释年龄、器官和 前列腺癌与饮食相关的特异性。