The study of novel miRNA in lung cancer initiation and metastasis

描述(申请人提供)：在美国，肺癌是男性和女性第二常见的癌症，死于肺癌的人比其他任何恶性肿瘤都多。这些死亡中的大多数是由与转移疾病相关的并发症引起的。不幸的是，大多数肺癌是在癌症转移后发现的。因此，确定调控肺癌发展的基因，尤其是肺癌转移的基因是非常必要的。为此，我们已经确定了在人类肺腺癌细胞系和非小细胞肺腺癌患者中表达改变的新型miRNA，非小细胞肺腺癌是最常见的肺癌类型。我们已经确定了与肺腺癌的生长、迁移和侵袭有关的特定miRNA。值得注意的是，这些miRNA在乳腺癌中具有相反的作用，突出了对 这些基因。我们建议研究这些miRNA在肺腺癌发展和转移中的作用，并确定它们作为诊断和复发预测的假定生物标记物的有效性。在目标1中，我们将确定特定的miRNA在肺腺癌增殖、迁移和侵袭中的作用及其影响的下游蛋白。在目标2中，我们将利用小鼠模型来确定这些新基因在肺腺癌发生和转移中的作用。在目标3中，我们将定义预测人类肺腺癌发展和复发的miRNA以及负责这些过程的蛋白质。我们将采取多种互补的方法，利用分子生物学、细胞生物学、生物化学和小鼠建模，以及对患者腺癌样本的分析来进行研究。这些研究将极大地扩大对调节肺腺癌发生和发展的分子事件的理解。拟议的实验结果也将通过确定新的治疗靶点和潜在的生物标记物来改善诊断和预测肺癌结果，从而具有临床意义。这项工作将在范德比尔特大学医学中心进行，范德比尔特大学医学中心是美国顶级生物医学研究机构之一。范德比尔特提供了一个出色的支持性培训环境，使我能够实现提出的研究目标，并获得实现我在科学领域的职业目标所需的培训。在我的博士后培训期间，我将获得成为一名成功的独立癌症生物学家所必需的关键知识和技能。范德比尔特有许多优秀的研讨会和众多的专业发展服务和机会，专门为促进博士后研究员成为独立调查人员而提供。我的导师和赞助人Christine M.Eischen博士将提供个性化的一对一培训，帮助我实现目标。完成这项国家研究服务奖培训计划将是至关重要的，为我提供所需的技能，以实现我作为一名研究上皮癌生物学的独立调查员的职业目标。 公共卫生相关性：这个项目将调查新发现的基因的功能及其在肺癌中的作用，肺癌是美国癌症死亡的主要原因。这些研究将扩大我们对肺癌生物学和调节这种疾病的发展和进展的分子事件的了解。拟议的实验结果可能会确定新的治疗目标和潜在的生物标记物，以改进诊断和疾病结果预测。

DESCRIPTION (provided by applicant): In the United States, lung cancer is the second most common cancer for both men and women, and more people die from lung cancer than any other malignancy. The majority of these deaths arise from complications associated with metastatic disease. Unfortunately, the majority of lung cancers are found after the cancer has metastasized. Thus, it is imperative to identify the genes that regulate the development, and especially the metastasis, of lung cancers. To this end, we have identified novel miRNA that have altered expression in human lung adenocarcinoma cell lines and patients with non-small cell lung adenocarcinoma, the most common type of lung cancer. We have identified specific miRNA that contribute to lung adenocarcinoma growth, migration, and invasion. Notably, these miRNA have the opposite effect in breast carcinoma, highlighting a cellular context specificity for these genes. We propose to investigate the role of these miRNA in lung adenocarcinoma development and metastasis, as well as determine their utility as putative biomarkers for diagnosis and relapse prediction. In Aim 1, we will determine the role for specific miRNA in lung adenocarcinoma proliferation, migration, and invasion and the downstream proteins affected by them. In the Aim 2, we will determine the contribution of these novel genes in lung adenocarcinoma initiation and metastasis in vivo using mouse models. In Aim 3, we wil define the miRNA that predict human lung adenocarcinoma development and relapse and the proteins responsible for these processes. We will take multiple complementary approaches that utilize molecular biology, cell biology, biochemistry, and mouse modeling, as well as analysis of patient adenocarcinoma samples for our studies. These studies will significantly expand understanding of the molecular events that regulate the development and progression of lung adenocarcinoma. The results of the proposed experiments will also have clinical relevance by identifying new therapeutic targets and potential biomarkers for improved diagnosis and lung cancer outcome prediction. This work will be conducted at Vanderbilt University Medical Center, one of the nation's top biomedical research institutions. Vanderbilt provides an outstanding supportive training environment that will allow me to meet the goals of the research proposed and gain the training necessary to achieve my career goals in science. During my postdoctoral training here, I will gain critical knowledge and skills essential to my becoming a successful independent cancer biologist. There are many outstanding seminars and numerous professional development services and opportunities offered at Vanderbilt specifically for advancing postdoctoral fellows toward becoming independent investigators. My mentor and sponsor, Dr. Christine M. Eischen, will provide the personalized one-on-one training that will assist me in reaching my goals. Completing this National Research Service Award training plan will be essential in providing me with the skills needed for me to achieve my career goal of conducting research as an independent investigator studying epithelial cancer biology. PUBLIC HEALTH RELEVANCE: This project will investigate the function of newly discovered genes and their role in lung cancer, the leading cause of cancer deaths in the United States. These studies will expand our knowledge of lung cancer biology and the molecular events that regulate the development and progression of this disease. The results of the proposed experiments will likely identify new therapeutic targets and potential biomarkers for improved diagnosis and disease outcome prediction.