The Sox9/NFIA Transcriptional Network In Malignant Glioma

 应聘者描述(由申请人提供)：应聘者从德克萨斯大学西南医学中心综合生物学系获得博士学位后，我在实验室或在德克萨斯州休斯敦的贝勒医学院攻读李秀坤博士的博士后职位，在此期间，我研究了在发育中的脊髓中协调轴突引导因子表达的转录程序。我在李实验室的工作得到了NIH为代表不足的少数族裔提供的补充拨款的支持。为了将我的职业轨迹推向更具翻译性的研究领域，我在贝勒医学院德宁博士的实验室担任了第二个博士后职位，我在那里工作了三年。我现在正在申请更高级的奖学金/奖励，并开始迈出建立自己的研究计划的第一步。我目前的工作是出于将我在发育生物学方面的技能和专业知识与基于疾病的肿瘤发生模型相结合的兴趣。获得NCI导师研究科学家发展奖(K01)将使我能够获得额外的概念/技术培训，并继续我在申请中概述的职业发展活动，如期刊俱乐部、研讨会、 和会议。有了这些额外的培训，我将能够在一家排名较高的机构寻求一个独立的研究职位。我的整个职业目标是启动并维持在胶质细胞谱系发育和胶质瘤发生的转录调控方面的成功研究生涯。我的职业指导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；完成职业发展活动，这将启动我的独立研究计划和资金。我希望以翻译应用为最终目标，为理解胶质细胞生物学和胶质瘤的发生做出重大贡献。环境贝勒医学院(BCM)是一家主要的研究机构，致力于研究和寻找新的治疗方法和治疗疾病的方法。作为细胞和基因治疗(CAGT)以及干细胞和再生医学中心(STAR)的一员，我将能够接触到在流式细胞术和基因组/RNA图谱方面具有专业知识的大量设备和广泛的核心设施。CAGT和STAR中心在翻译研究方面有着悠久的历史；教职员工的兴趣范围广泛，包括免疫疗法和干细胞生物学。这些中心鼓励成员之间的互动和合作，为我提供了一个丰富的环境，供我进行额外的科学培训。CAGT特别适合于研究胶质瘤发生，因为几名在胶质瘤生物学和脑瘤免疫治疗方法方面具有特定专业知识的教职员工已经承诺支持我提出的项目。研究在Deneen实验室期间，我研究了发育胶质发生的转录调控，并开始将这些发育概念转化为胶质瘤的研究。我已经确定了一个由两个转录因子Sox9和NFIA组成的转录级联，它们协调发育中的脊髓中胶质形成的启动。此外，我还在少突胶质细胞和多发性硬化症中发现了NFIA的转录功能。目前，我正在更详细地研究Sox9和NFIA之间的关系，并假设Sox9和NFIA之间的发育关系在胶质瘤形成过程中保持不变。这里提出的实验旨在研究恶性胶质瘤中的这种关系。我利用一种高度创新和新颖的小鼠胶质瘤模型，这种模型可以在3周内迅速产生恶性胶质瘤，并结合对原代人类胶质瘤细胞系的互补研究，研究NFIA和Sox9在胶质瘤发生中的作用。对发育决定因子转录调控在脑胶质瘤发生中的重要性的研究才刚刚开始。我提出的使用芯片序列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一个平台，研究发育程序和胶质瘤形成之间的关系。我相信，该项目中概述的研究将有助于从根本上理解胶质发生和胶质瘤的发生，并将与人类胶质瘤相关。

 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.