Sleeping Beauty for cancer gene discovery

描述（由申请人提供）：我的主要研究重点是使用一种强大的新型插入诱变剂，睡美人（SB）转座子系统，以解决癌症遗传学中的基本问题。我以前的训练集中在开发SB用于小鼠癌症基因的前向遗传筛查。在我自己的研究实验室里，我想进行更多的实验，研究SB鉴定的基因在人类癌症中的作用，最初集中在BRAF癌基因上。此外，我想调整SB系统来阐明人类癌症治疗中的一个基本问题的遗传学，即治疗抗性。我建议使用SB系统，以确定基因参与获得性耐药BAY 43-9006，激酶抑制剂，现在显示在临床试验中作为一种化疗药物的承诺。此外，我建议使用SB系统来识别由于对激素消融疗法获得性不敏感而导致的前列腺癌进展中涉及的基因。将在人类癌症模型中测试所鉴定的基因在治疗抗性中的作用。这些项目将在我作为明尼苏达大学博士后研究员的最后一年启动。SB系统最初是为脊椎动物遗传学开发的， 我导师的实验室是Arnold和美宝贝克曼转座子研究中心的成员。作为癌症中心的一员，我可以使用几个核心设施，为这里提出的项目提供支持。在我作为博士后研究员的最后一年，我将申请有强大研究项目的大学的助理教授职位。我的长期职业目标是建立一个研究实验室，使用新的遗传方法来研究人类癌症生物学和治疗。 这项拟议中的研究采用了一种新技术，即睡美人转座子系统，来识别参与癌症起始和治疗抗性进展的基因。这项研究与人类健康有关，因为了解疾病的遗传学是开发更有效的患者特异性疗法的重要一步。此外，我们假设这项技术将有助于创建更好的人类癌症模型，这将有助于药物发现和测试。

DESCRIPTION (provided by applicant): My primary research focus is to use a powerful novel insertional mutagen, the Sleeping Beauty (SB) transposon system, to address fundamental questions in cancer genetics. My training has previously focused on developing SB for forward genetic screens for cancer genes in mice. In my own research laboratory, I would like to pursue additional experiments studying the role of genes identified by SB in the context of human cancer, initially focusing on the BRAF oncogene. In addition, I would like to adapt the SB system to elucidate the genetics of a fundamental problem in human cancer treatment, namely therapy resistance. I propose to use the SB system to identify genes that are involved in acquired resistance to BAY 43-9006, a kinase inhibitor now showing promise in clinical trials as a chemotherapeutic agent. In addition, I propose to use the SB system to identify genes involved in prostate cancer progression as a result of acquired insensitivity to hormone ablation therapies. The role of identified genes in therapy resistance will be tested in human cancer models. These projects will be initiated in my final year as a post-doctoral fellow at the University of Minnesota. The SB system was originally developed for vertebrate genetics at the University of Minnesota, and my mentor's laboratory is a member of the Arnold and Mabel Beckman Center for Transposon Research. As a member of the Cancer Center, I have access to several Core facilities that will provide support to the projects proposed here. During my final year as a post-doctoral fellow, I will apply to assistant professor positions at Universities with strong research programs. My long-term career goal is to establish a research laboratory that uses novel genetic approaches to study human cancer biology and treatment. The proposed research employs a novel technology, the Sleeping Beauty transposon system, to identify genes involved in both cancer initiation and progression to therapy resistance. This research is relevant to human health as understanding the genetics of the disease is an important step toward developing more effective, patient-specific therapies. In addition, we hypothesize that this technology will be useful for creating better models of human cancer that will be useful for drug discovery and testing.