The Sox9/NFIA Transcriptional Network In Malignant Glioma

 描述（由申请人提供）：候选人毕业后，博士学位。在德克萨斯大学西南医学中心综合生物学系毕业后，我在贝勒医学院（休斯顿，德克萨斯州）的Soo-Kyoung Lee博士的实验室从事博士后工作，在此期间，我研究了在发育中的脊髓中协调轴突导向因子表达的转录程序。我在李实验室的工作得到了美国国立卫生研究院为少数民族提供的补充拨款的支持。为了将我的职业轨迹转向更具转化性的研究领域，我在贝勒医学院的Deneen博士实验室担任了第二个博士后职位，在那里我工作了三年。我现在正在申请更多的高级奖学金/奖项，并开始采取初步措施，建立自己的研究计划。我目前的工作是由我的技能和专业知识相结合，在发育生物学与肿瘤发生的疾病为基础的模型的兴趣驱动。获得NCI指导研究科学家发展奖（K 01）将使我能够获得额外的概念/技术培训，并从事我在此申请中概述的职业发展活动，如期刊俱乐部，研讨会， 和会议。通过这次额外的培训，我将能够在一个高排名的机构从事独立的研究工作。我的总体职业目标是启动和维持一个成功的研究生涯在胶质细胞谱系的发展和胶质瘤的转录调控。我的指导职业奖的目标包括在高影响力的期刊上发表三篇第一作者论文;学习癌症生物学领域的概念和研究技术;并完成职业发展活动，这将启动我的独立研究计划和资金。我希望能对胶质细胞生物学和胶质瘤发生的理解做出重大贡献，最终目标是翻译应用。贝勒医学院（Baylor College of Medicine）是一所首屈一指的研究机构，致力于研究和寻找新的治疗方法和治愈疾病的方法。作为细胞和基因治疗（CAGT）以及干细胞和再生医学中心（星星）的一部分，我将有机会使用大量设备和各种核心设施，这些设施具有流式细胞术和基因组/RNA分析方面的专业知识。CAGT和星星中心有着悠久的转化研究历史;教师有着广泛的兴趣，包括免疫治疗和干细胞生物学。中心鼓励成员之间的互动和合作，这为我的额外科学培训提供了丰富的环境。CAGT特别适合研究胶质瘤的发生，因为几位在胶质瘤生物学和脑肿瘤免疫治疗方法方面具有特定专业知识的教职员工致力于支持我提出的项目。研究在Deneen实验室工作期间，我研究了发育性胶质细胞生成的转录调控，并开始将这些发育概念转化为胶质细胞瘤的研究。我已经确定了一个由两个转录因子组成的转录级联，Sox 9和NFIA，它们协调了发育中脊髓胶质细胞生成的启动。此外，我还发现了NFIA在少突胶质细胞和多发性硬化症中的转录功能。目前，我正在更详细地研究Sox 9/NFIA的关系，并假设Sox 9和NFIA之间的发育关系在胶质瘤发生过程中得到维持。这里提出的实验是为了检查这种关系在恶性胶质瘤。我利用一个高度创新和新颖的胶质瘤小鼠模型，迅速产生（3周内）恶性胶质瘤，结合在原代人类胶质瘤细胞系的互补研究，研究NFIA和Sox 9在胶质瘤肿瘤发生中的作用。发育决定因子的转录调控在胶质瘤发生中的重要性才刚刚开始被探索。我提出的使用ChIP-seq和基因表达谱技术相结合的恶性胶质瘤转录谱实验将作为研究发育程序和胶质瘤发生之间关系的平台。我相信，在这个项目中概述的研究可以有助于胶质细胞和胶质瘤肿瘤发生的基本理解，并将与人类胶质瘤。

 DESCRIPTION (provided by applicant): Candidate Upon graduating with a Ph.D. from the integrative biology department of the University of Texas Southwestern Medical Center, I pursued a post-doctoral position in the lab or Dr. Soo-Kyoung Lee at Baylor College of Medicine (Houston, TX), during which I studied the transcriptional programs that orchestrate the expression of axon guidance factors in the developing spinal cord. My work in the Lee lab was supported by the supplemental grant for underrepresented minorities from the NIH. To move my career trajectory toward a more translational area of study, I undertook a second post-doctoral position in the laboratory of Dr. Deneen at Baylor College of Medicine, where I have worked for three years. I am now applying for more senior fellowships/awards and beginning to take the initial steps toward establishing my own research program. My current work is driven by an interest in combining my skills and expertise in developmental biology with disease-based models of tumorigenesis. Obtaining the NCI Mentored Research Scientist Development Award (K01) will allow me to gain both the additional conceptual/ technical training and pursue the career development activities I have outlined in this application such as, journal clubs, seminars, and conferences. With this additional training I will be able to pursue an independent research position at a highly ranked institution. My overall career goal is to initiate and sustain a successful research career in glial lineage development and transcriptional regulation of gliomagenesis. My goals for the mentored career award include publishing three first-author papers in high-impact journals; learn concepts and research techniques in the area of cancer biology; and to complete the career development activities that will launch my independent research program and funding. I hope to make a significant contribution to the understanding of glial cell biology and glioma tumorigenesis with the ultimate goal of translational application. Environment Baylor College of Medicine (BCM) is a premier research institution with a strong commitment to research and finding new treatments and cures for disease. As a part of the Cell and Gene Therapy (CAGT), and Stem Cells and Regenerative Medicine Center (STaR), I will have access to a large array of equipment and a wide range of core facilities with expertise in Flow Cytometry and genomic/RNA profiling. The CAGT and STaR centers have a long history of translational research; faculty have a diverse range of interests including immunotherapy and stem cell biology. The centers encourage interaction and collaboration among its members which provides a rich environment for my additional scientific training. The CAGT is particularly well suited for studying gliomagenesis as several faculty members with specific expertise in glioma biology and immunotherapy approaches to brain tumors have committed to supporting my proposed project. Research During my time in the Deneen lab I have studied the transcriptional regulation of developmental gliogenesis and have begun to translate these developmental concepts to the study of glioma. I have identified a transcriptional cascade consisting of two transcription factors, Sox9 and NFIA, which orchestrate the initiation of gliogenesis in the developing spinal cord. Furthermore, I have found transcriptional functions for NFIA in oligodendrocytes and multiple sclerosis. Currently, I am examining the Sox9/NFIA relationship in more detail and hypothesize that the developmental relationship between Sox9 and NFIA is maintained during gliomagenesis. The experiments proposed here are geared toward examining this relationship in malignant glioma. I utilize a highly innovative and novel mouse model of glioma which rapidly generates (within 3 weeks) malignant gliomas, combined with complementary studies in primary human glioma cell lines to study the roles of NFIA and Sox9 in glioma tumorigenesis. The importance of transcriptional regulation of developmental determining factors in glioma tumorigenesis is just beginning to be explored. My proposed transcriptional profiling experiments in malignant gliomas using a combination of ChIP-seq and gene expression profiling technologies will serve as a platform for studying the relationship between developmental programs and gliomagenesis. I believe that the research outlined in this project can contribute to the fundamental understanding of gliogenesis and glioma tumorigenesis and will have relevance to human gliomas.