Epigenetics of Melanoma Metastasis

总结 恶性黑色素瘤是一种高度侵袭性的疾病，死亡率高得惊人。虽然我们 虽然我们对黑色素瘤的遗传决定因素有了实质性的了解，但我们对黑色素瘤的遗传决定因素的了解非常有限。 黑色素瘤转移的表观遗传机制因此，这项建议旨在确定表观遗传 修饰和转移过程中涉及的因素，并了解它们如何赋予转移 潜在的癌细胞。长期目标是能够识别新的药物靶点并开发诊断药物。 测定。在我之前的培训中，我获得了一些研究表观遗传机制的经验 在发展和结肠癌的开始。我很想利用这些经验来解决这个问题 使用黑色素瘤系统的重要问题。Chin实验室在利用基因组数据集和大规模 筛选以了解转移和多种黑色素瘤小鼠模型的可用性， 完美的环境来解决我感兴趣的科学问题。在这个提议中，我的目的是了解 利用新的表观基因组的黑色素瘤细胞的促转移特性的表观遗传机制 方法，强大的体内筛选和小鼠模型。在目标1中，我将阐明亲- RNF 2的转移作用，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景观，以确定受影响的细胞系统 由促转移的表观遗传变化引起的。在目标3中，我将采取无偏的方法，并使用体内大规模 在小鼠中进行筛选以鉴定表观遗传转移启动子和抑制子。“命中”机制 将按照目标1和目标2中用于RNF 2的方式对来自该屏幕的数据进行研究。总的来说，我在表观基因组学方面的训练， 小鼠建模和大规模的体内屏幕将磨练我的科学技能，为我成功地 独立的职业生涯。在我的独立阶段，我将确定新的转移抑制机制 和通过提出的筛选鉴定的启动子。此外，我将建立小鼠和斑马鱼模型， 这些基因作为药物靶点的能力。最后，通过这些研究，我希望找到新的药物靶点， 表观遗传作用和可能的表观遗传标记（在特定的基因组位点上），用于设计新的诊断 方法.

Summary 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.