Investigating the role of retrotransposons in hematopoietic neoplasias.

描述(申请人提供)：研究反转录转座子在造血肿瘤中的作用。本提案描述了一项为期五年的培训计划，旨在发展恶性血液病的遗传基础方面的学术生涯。我是一名内科科学家，在贝勒医学院完成了遗传学博士研究，重点是生殖生物学和体内肿瘤修饰物，这是医学博士合并项目的一部分。我还在约翰·霍普金斯医院完成了临床病理学/实验室医学的实习，目前我是该医院的临床血液病理学研究员。我将在2008年7月完成这项临床研究。 在获奖期间，我将通过发展我的博士后研究和约翰·霍普金斯大学医学院的机构优势，确立自己作为一名独立研究员的地位。许多优秀的个人和资源将为促进我的研究和职业发展的成功提供一个特殊的环境。这项工作将特别涉及我的主要部门，病理学系的合作者，以及癌症中心的Civin实验室和高通量生物中心的Boeke实验室的共同指导。职业发展计划将建立在我在古典遗传学方面的强大背景之上，增加现代基因组学前沿的教学培训和主要研究经验。拟议的工作将专注于对初级患者样本的分析，这不是我以前的经验，将使我更好地定位于执行具有翻译潜力的未来研究。 我的研究将集中在：(I)了解血液系统恶性肿瘤中重复元件稳定的表观遗传学，以及(Ii)应用我在住院期间开发的反转录转座子定位策略来研究这些移动元件如何在肿瘤发生和肿瘤进展中起作用。由线重复转位引起的插入突变是癌症中遗传性疾病和体细胞突变的已知原因。然而，转座子参与癌症发展的程度尚未得到重视，因为到目前为止还没有全基因组的作图策略可用。这个项目既非常创新又可行，有可能为我们对肿瘤生物学的欣赏增加一个重要的维度。此外，如果LINE不稳定性对癌症复发和治疗耐药有意义，这一知识可能会转化为抗逆转录病毒治疗在癌症患者中的应用。

DESCRIPTION (provided by applicant): Investigating the role of retrotransposons in hematopoietic neoplasias. This proposal describes a five-year training program for development of an academic career in the genetic basis of hematologic malignancies. I am a physician-scientist, having completed doctoral studies in genetics with a focus on reproductive biology and in vivo tumor modifiers at Baylor College of Medicine as part of the combined M.D., Ph.D. program. I have also completed a residency in clinical pathology/laboratory medicine at Johns Hopkins Hospital where I am currently a clinical hematopathology fellow. I will complete this clinical fellowship in July 2008. I will establish myself as an independent investigator during this award period by developing my postdoctoral research and involving institutional strengths of the Johns Hopkins University School of Medicine. Many outstanding individuals and resources will contribute to a special environment for promoting the success of my research and career development. This effort will specifically involve collaborators within my primary department, the Department of Pathology, and co-mentorship from the Civin laboratory in the Cancer Center and the Boeke laboratory in the High Throughput Biology Center. The career development plan will build on my strong background in classical genetics, adding didactic training and primary research experiences in the forefront of modern genomics. The proposed work will focus on analysis of primary patient samples, which is outside my prior experience and will better position me to perform future studies with translational potential. My research will focus on: (i.) understanding the epigenetics of repetitive element stabilization in hematopoietic malignancies, and (ii.) applying a retrotransposon mapping strategy that I developed during my residency to investigate how these mobile elements contribute to oncogenesis and tumor progression. Insertional mutations caused by LINE repeat transposition are known causes of both heritable disease and somatic mutation in cancer. However, the extent of transposon participation in cancer development is not appreciated because genome-wide mapping strategies have not been available until now. This project is both very innovative and feasible, with potential to add an important dimension to our appreciation of tumor biology. Moreover, if LINE instability contributes meaningfully to cancer recurrence and resistance to therapeutics, this knowledge might be translated to application of antiretroviral therapies in cancer patients.