Epigenetics, Metabolism and Cancer

表观遗传学、新陈代谢和癌症

• 批准号: 10712221
• 负责人: Ali Shilatifard
• 金额: $ 16.22万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2028-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10712221
• 关键词: Epigenetic Process; Malignant Neoplasms; Metabolism

Project Summary It is now well accepted that epigenetic and metabolic factors are major drivers of tumorigenesis and the link between the two pathways will be central in cancer therapy. The intimate connection between epigenetics and metabolism is most readily realized by the cofactors for epigenetic modifiers being key inputs and products for metabolic pathways. Acetyl coenzyme A, in addition to its role in oxidative phosphorylation, is the source of acetate used by histone acetyltransferases. S-adenosyl methionine, produced by the folate and methionine metabolic pathways, is the donor for histone and DNA methylation. Alpha ketoglutarate, a TCA cycle metabolite, is a cofactor for histone demethylases of the Jumonji and LSD families, as well as for the ten-eleven translocase (TET) Tet methylcytosine dioxygenase family that is involved in DNA demethylation. A direct link between the metabolic and epigenetic pathways in cancer was the identification of mutations in isocitrate dehydrogenases IDH1 and IDH2 in myeloid malignancies, which also frequently exhibits TET2 mutations. The IDH mutations were found to be gain-of-function mutations, converting alpha ketoglutarate to D(R)-2-hydroxyglutarate, which inhibits the TET enzymes. Based on the deep relationship of epigenetics and metabolism in tumorigenesis and the growing number of methods to investigate these processes, we propose to create a timely, rigorous, and state- of-the-art training program at Northwestern University Feinberg School of Medicine to allow postdoctoral fellows to gain the knowledge and skills to develop their own productive cancer research programs. The program will introduce innovative courses combining classwork and lab work in epigenetics, metabolism, and related data analysis skills. Trainees will have an individual training plan, which will include co-mentors to fully cover the broad expertise needed for carrying out projects that bridge epigenetics and metabolism. Additionally, outstanding investigators, hosted by trainees, will be brought to Northwestern Medicine throughout the year covering topics in epigenetics and metabolism. An annual research day will be joined by internal and external advisory members to monitor and advise to ensure the success of this training program. Although trainees will only be supported by the training grant for two years, we strongly encourage all graduates of the training grant to continue to participate in many of these activities throughout their postdoctoral career. Based on the strong investment of Northwestern University into epigenetics and metabolism, the track record of the program's preceptors, and the institutional investments in this program, there is great potential for facilitating the development of outstanding future investigators in cancer epigenetics and metabolism.

项目摘要 现在，表观遗传和代谢因素是肿瘤发生的主要驱动因素和联系 这两种途径之间将是癌症治疗的中心。表观遗传学和 代谢最容易被辅助因子实现，表观遗传修饰剂是关键输入和产品 代谢途径。除了其在氧化磷酸化中的作用外，乙酰辅酶A除了其在氧化磷酸化中的作用，还是 组蛋白乙酰转移酶使用的乙酸盐。 S-腺苷蛋氨酸，由叶酸和蛋氨酸产生 代谢途径是组蛋白和DNA甲基化的供体。 Alpha Ketoglutarate，TCA循环代谢物， 是Jumonji和LSD家族的组蛋白脱甲基酶的辅因子，以及十个时期的易位酶 （TET）参与DNA脱甲基化的TET甲基胞嘧啶二加氧酶家族。在 癌症中的代谢和表观遗传途径是鉴定异急促脱氢酶突变的鉴定 髓样恶性肿瘤中的IDH1和IDH2也经常表现出TET2突变。 IDH突变是 被发现是功能收益的突变，将α酮谷酸酯转换为d（r）-2-羟基戊二酸，它抑制 TET酶。基于表观遗传学和代谢在肿瘤发生和 越来越多的研究这些过程的方法，我们建议创建及时，严格和状态的方法 西北大学Feinberg医学院的艺术培训计划允许博士后研究员 获得知识和技能来开发自己的生产癌症研究计划。该程序将 介绍将课堂工作和实验室工作结合在表观遗传学，代谢和相关数据中的创新课程 分析技能。受训人员将制定一个个人培训计划，其中包括联合给予者，以完​​全覆盖 进行弥合表观遗传学和代谢的项目所需的广泛专业知识。此外， 由学员主持的杰出调查员将全年被带到西北医学 涵盖表观遗传学和代谢的主题。年度研究日将由内部和外部加入 咨询成员监视和建议以确保该培训计划的成功。虽然学员会 我们仅得到两年的培训补助金的支持，我们强烈鼓励所有培训补助金的毕业生 在整个博士后职业中继续参加许多此类活动。基于强 对西北大学的投资投资于表观遗传学和代谢，该计划的往绩记录 主持人以及该计划的机构投资，有很大的潜力来促进 发展癌症表观遗传学和代谢的未来未来研究者。