Epigenetics of Melanoma Metastasis

描述（由申请人提供）：恶性黑色素瘤是一种高度侵袭性疾病，死亡率高得惊人。虽然我们对黑色素瘤的遗传决定因素已经有了实质性的了解，但我们对黑色素瘤转移的表观遗传机制的了解非常有限。因此，该提案旨在确定参与转移过程的表观遗传修饰和因子，并了解它们如何赋予癌细胞转移潜力。长期目标是能够识别新的药物靶点并开发诊断分析。在我以前的培训中，我在研究发育和结肠癌启动过程中的表观遗传机制方面获得了一些经验。我热衷于应用一些经验，解决这个重要的问题，使用黑色素瘤系统。Chin实验室在利用基因组数据集和大规模筛选来了解转移和多种黑色素瘤小鼠模型的可用性方面的专业知识为我提供了一个完美的环境来解决我感兴趣的科学问题。在这个建议中，我的目的是了解表观遗传机制的黑色素瘤细胞的促转移特性，利用新的表观基因组学方法，强大的体内筛选和小鼠模型。在目标1中，我将阐明RNF2的促转移作用的机制，并评估其作为药物靶点的潜力。在目标2中，我将确定非转移细胞和促转移细胞的表观基因组景观，以确定受促转移表观遗传变化影响的细胞系统。在目标3中，我将采用无偏的方法，在小鼠体内进行大规模筛选，以确定表观遗传转移的启动子和抑制子。将按照目标1和目标2中RNF2的情况，研究这一筛选的“命中”机制。总的来说，我在表观基因组方法，小鼠建模和大规模体内筛选方面的培训将磨练我的科学技能，为我成功的独立职业生涯做好准备。在我的独立阶段，我将确定新的转移抑制剂和促进剂的机制，确定了建议的屏幕。此外，我将建立小鼠和斑马鱼模型，以评估这些基因作为药物靶点的能力。最后，通过这些研究，我希望确定具有表观遗传作用的新药物靶点和可能的表观遗传标记（在特定基因组位点上），以用于设计新的诊断方法。

DESCRIPTION (provided by applicant): Malignant melanoma is a highly aggressive disease with alarmingly high mortality rates. Although we have gained substantial understanding of genetic determinants of the melanoma, we have very limited knowledge of epigenetic mechanisms underlying melanoma metastasis. Therefore, this proposal aims to identify epigenetic modifications and factors involved in the process of metastasis and understand how they impart metastatic potential to cancer cells. The long term-goal is to be able to identify novel drug targets and develop diagnostic assays. During my previous training, I have gained some experience in studying epigenetic mechanisms during development and colon cancer initiation. I am keen to apply some of this experience in addressing this vital question using melanoma system. The Chin lab's expertise in utilizing genomic datasets and large scale screens to understand metastasis and the availability of multiple mouse models of melanoma provides me a perfect environment to address the scientific question of my interest. In this proposal I aim to understand epigenetic mechanisms underlying pro-metastatic properties of melanoma cells utilizing new epigenomic methods, powerful in vivo screens and mouse models. In Aim 1, I will elucidate the mechanism of the pro- metastatic action of RNF2 and assess its potential as a drug target. In Aim 2, I will determine the epigenomic landscape of non-metastatic cells and pro-metastatic cells in an effort to identify the cellular systems affected by pro-metastatic epigenetic changes. In Aim 3, I will take unbiased approach and use in vivo large scale screens in mice to identify epigenetic metastasis-promoters and suppressors. The mechanism for the 'hits' from this screen will be studied as used for RNF2 in Aim 1 and 2. Overall, my training in epigenomic methods, mouse modeling and large scale in vivo screens will hone my scientific skills to prepare me for a successful independent career. In my independent phase, I will identify the mechanism of new metastasis-suppressors and promoters identified by proposed-screens. In addition, I will build mouse and zebrafish models to assess the ability of these genes as drug targets. In the end, by these studies I hope to identify new drug targets with epigenetic roles and possible epigenetic marks (on specific genomic loci) to use for devising new diagnostic methods.