Epigenetics, Metabolism and Cancer

项目摘要 现在人们普遍认为，表观遗传和代谢因素是肿瘤发生和联系的主要驱动因素 这两条途径之间的联系将是癌症治疗的核心。表观遗传学和表观遗传学之间的密切联系 新陈代谢最容易通过表观遗传修饰物的辅因子来实现，表观遗传修饰物是 代谢途径。乙酰辅酶A除了在氧化磷酸化中的作用外，还是 组蛋白乙酰转移酶使用的醋酸酯。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。α-酮戊二酸，一种三氯乙酸循环代谢物， 是Jumonji和LSD家族的组蛋白去甲基酶以及10-11转位酶的辅助因子 (Tet)参与DNA去甲基化的Tet甲基胞嘧啶双加氧酶家族。两国之间的直接联系 癌症中的代谢和表观遗传途径是异柠檬酸脱氢酶突变的鉴定 髓系恶性肿瘤中的IDH1和IDH2，也经常表现出TET2突变。IDH突变为 发现是功能获得突变，将α-酮戊二酸转化为D(R)-2-羟基戊二酸，从而抑制 Tet酵素。基于表观遗传学和新陈代谢在肿瘤发生中的深层关系和 越来越多的方法来调查这些过程，我们建议创建一个及时、严格和状态- 西北大学范伯格医学院最先进的培训计划允许博士后研究员 获得知识和技能，开发自己富有成效的癌症研究项目。该计划将 引入创新课程，结合表观遗传学、新陈代谢和相关数据的课堂作业和实验室工作 分析技巧。学员将有个人培训计划，其中将包括共同导师，以全面覆盖 开展连接表观遗传学和新陈代谢的项目所需的广泛专业知识。另外， 由实习生主持的优秀研究人员将全年被带到西北医学 涵盖表观遗传学和新陈代谢方面的主题。一年一度的研究日将由内部和外部参加 顾问成员监督并提供建议，以确保培训计划的成功。尽管实习生将 只有两年的培训补助金支持，我们强烈鼓励所有毕业生的培训补助金 在他们的博士后生涯中继续参与其中的许多活动。基于强者 西北大学对表观遗传学和新陈代谢的投资，该项目的跟踪记录 教官，以及在这个项目中的机构投资，有很大的潜力促进 癌症表观遗传学和新陈代谢领域未来杰出研究人员的发展。

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.