A New Target for Chromatin Remodeler Defects in Cancer

癌症染色质重塑缺陷的新靶点

• 批准号: 10650812
• 负责人: Cheryl L. Walker
• 金额: $ 93.2万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-01 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10650812
• 关键词: Adult; Award; Cell physiology; Cells; Chromatin; Code; Cytoskeleton; Cytoskeleton Alteration; Data; Defect; Development; Environmental Carcinogens; Environmental Exposure; Epigenetic Process; Genes; Genomic Instability; Goals; Histone Code; Laboratories; Malignant Neoplasms; Methylation; Microtubules; Mitotic spindle; Needles; Neoplasm Metastasis; Play; Proteins; Reader; Reading; Reporting; Research; Research Personnel; Tubulin; Tumor Suppressor Genes; Writing; anticancer research; blind; cancer risk; cancer type; chemical carcinogen; design; environmental carcinogenesis; epigenome; experimental study; frontier; insight; programs; protein function; therapy development

My laboratory has pioneered new research directions in environmental carcinogenesis for the past 25 years. We identified new targets for chemical carcinogens, new functions for “old” tumor suppressor genes, and elucidated the first mechanism by which environmental exposures during development could reprogram the epigenome to increase cancer risk in adulthood. It is my goal to continue to advance the field of cancer research by tackling challenging questions, rather than performing incremental research, which while safe, does little to “move the needle”. My objective for obtaining this R35 Outstanding Investigator Award is to focus my efforts on an exciting new discovery, which represents a paradigm shift in how we look at chromatin remodeler defects in cancer. As an unexpected off-shoot of our research on how environmental carcinogens reprogram the epigenome, we discovered a new function for the cell’s epigenetic machinery, and a new way for defects in chromatin remodeler genes to drive cancer. The Overarching Hypothesis for this R35 application is that the coding machinery known for “reading, writing and erasing” epigenetic methyl marks on chromatin plays a second, equally important but heretofore unappreciated, coding function “reading, writing and erasing” methyl marks on the cytoskeleton. We reported (Park et al Cell 2016), and support with additional Preliminary Data, that many chromatin remodelers are actually dual-function proteins, participating in both the Histone Code of chromatin, and the Tubulin Code of microtubules. This insight sets the stage for a new paradigm, wherein the cell’s methylation machinery serves two coding functions, one on chromatin and one on the cytoskeleton. It opens new frontiers for understanding how cells utilize and regulate one machinery with two distinct, but equally important coding functions. This is of special importance for cancer research, as we have been blind to the fact that defects in chromatin remodeler genes can directly impact the cytoskeleton, for example, via mitotic spindle defects that drive genomic instability and cytoskeletal defects that alter mobility to promote metastasis. The experiments proposed in this application are designed to open new doors for understanding the impact of chromatin remodeler defects in cancer, and for the development of therapies with efficacy against both the epigenetic and cytoskeletal alterations caused by defects in genes that encode dual-function chromatin-cytoskeleton remodelers.

我的实验室开创了环境致癌的新研究方向 过去 25 年，我们确定了化学致癌物的新靶点，“老”肿瘤的新功能。 抑制基因，并阐明了在环境暴露期间的第一个机制 发育可以重新编程表观基因组以增加成年后患癌症的风险。 通过解决具有挑战性的问题来继续推进癌症研究领域，而不是 进行增量研究，虽然安全，但对“推动我的目标”作用不大。 获得 R35 杰出研究者奖是为了将我的精力集中在一个令人兴奋的新研究上 发现，这代表了我们如何看待染色质重塑缺陷的范式转变 作为我们关于环境致癌物如何重新编程的研究的一个意想不到的分支。 表观基因组，我们发现了细胞表观遗传机制的新功能，以及一种新方法 染色质重塑基因缺陷导致癌症的总体假设。 R35应用是以“读、写、擦除”着称的编码机器 染色质上的表观遗传甲基标记起着第二位的作用，同样重要，但迄今为止 未受重视的编码功能“读取、写入和擦除”上的甲基标记 我们报道了（Park et al Cell 2016），并提供了额外的初步数据支持， 许多染色质重塑蛋白实际上是双功能蛋白，参与 染色质的组蛋白密码和微管的微管蛋白密码为这一见解奠定了基础。 一种新的范式，因此细胞的甲基化机制具有两种编码功能，一种是 它为理解细胞如何利用染色质和细胞骨架开辟了新的领域。 并用两个不同但同样重要的编码功能来调节一台机器。 对于癌症研究特别重要，因为我们一直忽视染色质缺陷这一事实 重塑基因可以直接影响细胞骨架，例如通过有丝分裂纺锤体缺陷 导致基因组不稳定和细胞骨架缺陷，从而改变流动性以促进转移。 本申请中提出的实验旨在为理解打开新的大门 染色质重塑缺陷对癌症的影响，以及治疗方法的开发 对由基因缺陷引起的表观遗传和细胞骨架改变的功效 编码双功能染色质-细胞骨架重塑剂。