Targeting glioma stem cells by perturbation of telomere maintenance mechanisms

项目摘要 建议的研究是探索通过扰动治疗恶性胶质瘤的新的治疗机会。 胶质瘤干细胞的端粒维持机制。恶性胶质瘤对治疗的抵抗力很强 这在很大程度上是由于胶质瘤干细胞(GSCs)的存在，它具有取之不尽的自我更新和 扩散。我建议通过抑制端粒酶来靶向GSCs，因为GSCs的端粒酶水平更高 活性强于体细胞和其他非GSC肿瘤细胞。在目标1中，我将探索GSC对 端粒酶抑制与三个独立的模型系统。我还将测试抗端粒酶是否会增敏 综合治疗方案中的常规放疗和化疗。我之前的研究 研究表明，抗端粒酶将通过ALT(端粒替代延长)导致耐药性 机制，所以在目标2中，我将生成并描述依赖ALT机制的GSC，并将探索 靶向丙氨酸氨基转移酶弱以预防端粒酶耐药的可能性 心理治疗。越来越多的证据表明染色质重塑因子在细胞周期调控中的重要作用。 端粒，所以在目标3中，我将研究端粒酶+中端粒染色质重塑的机制。 和ALT+胶质瘤干细胞。从这一目的获得的信息将有助于我们理解ALT的性质 GSC的作用机制，并为靶向ALT+GSC提供新的治疗机会。这 建议的学习将帮助我形成一个强大的研究计划，我将利用该计划成立一个独立的教职员工。 在学术/医学研究机构的职位。为此，我的近期目标是继续 磨练我在小鼠遗传学、端粒生物学和干细胞生物学方面的技术技能，并扩大我的 具备肿瘤基因组学、生物统计学和翻译生物学方面的技能。在我的职业发展方面，我将是 致力于提高我的实验室管理技能，指导博士后和学生，科学写作和 演讲，以及寻求合作，等等，因为这些技能对我来说都是必不可少的 找到了一个教员的职位，并成功地成为一名PI。安德森癌症中心(MDACC)和罗纳德·德皮尼奥 实验室为我实现这些目标提供了良好的培训环境。即使德皮尼奥博士 他现在是MDACC的主席，他仍然承诺会把2.5%的精力投入到我的培训和职业发展上。我 还成立了一个由黄绵杰博士、容伟群博士组成的特别咨询委员会 还有陈俊杰博士。他们不仅将为我提议的研究提供技术支持，而且还将指导我 寻找教员职位，并作为一名独立调查员取得成功。在K99/R00培训的帮助下 格兰特，我将有一个良好的开端来实现我的长期目标，那就是继续探索基础和 癌症生物学中的翻译问题，包括端粒生物学和癌症干细胞生物学，作为实验室 在学术/医学研究机构担任所长，并作为 通过与其他科学家、医生和制药公司合作，具有团队精神。

Project Summary The proposed study is to explore novel therapeutic opportunities to cure malignant gliomas by perturbing telomere maintenance mechanisms in glioma stem cells. Malignant gliomas are highly resistant to treatment largely due to the existence of glioma stem cells (GSCs), which possess inexhaustible ability to self-renew and proliferate. I propose to target GSCs by inhibiting telomerase because GSCs have higher level of telomerase activity than somatic cells and other non-GSC tumor cells. With Aim 1, I will explore GSCs' response to telomerase inhibition with three independent model systems. I will also test whether anti-telomerase sensitizes conventional radiation therapy and chemotherapy in combinatorial therapy regimens. My previous study showed that anti-telomerase will lead to resistance through ALT (Alternative Lengthening of Telomeres) mechanisms, so in Aim 2 I will generate and characterize GSCs that rely on ALT mechanisms and will explore the possibility to target the weakness of ALT in order to prevent the resistance in response to anti-telomerase therapy. More evidence is pointing to the important function of chromatin remodeling factors in the regulation of telomeres, so in Aim 3, I will investigate the mechanisms of telomeric chromatin remodeling in telomerase+ and ALT+ glioma stem cells. The information obtained from this aim will help us understand the natures of ALT mechanisms in the GSC context and provide new therapeutic opportunities to target ALT+ GSCs. This proposed study will help me to form a strong research program, with which I will launch an independent faculty position in an academic/medical research institution. To that end, my immediate goals are to continue sharpening my technical skills in mouse genetics, telomere biology and stem cell biology and expanding my skills in oncogenomics, biostatistics and translational biology. In terms of my career development, I will be devoted to improve my skills on managing lab, mentoring postdocs and students, scientific writing and presentation, and seeking for collaborations, among others, because these skills are all essential for me to land a faculty position and succeed as a PI. MD Anderson Cancer Center (MDACC) and the Ronald DePinho laboratory provide an excellent training environment for me to achieve these goals. Even though Dr. DePinho is President of MDACC now, he still promises to devote 2.5% effort to my training and career development. I have also formed an extraordinary advisory committee composed of Dr. Mien-Chie Huang, Dr. Wai-Kwan Yung and Dr. Junjie Chen. They will not only provide me technical support for my proposed study, but also guide me to look for a faculty position and succeed as an independent investigator. With the help of K99/R00 training grant, I will have a good start to achieve my long term goals, which are to continue exploring basic and translational problems in cancer biology, including telomere biology and cancer stem cell biology, as a lab head in an academic/medical research institute and to contribute in developing novel cancer therapies as a team player by collaborating with other scientists, physicians and pharmaceutical companies.