Targeting glioma stem cells by perturbation of telomere maintenance mechanisms

项目摘要 这项研究旨在探索新的治疗机会，通过干扰治疗恶性胶质瘤。 胶质瘤干细胞端粒维持机制的研究进展恶性胶质瘤对治疗有很强的抵抗力 这主要是由于神经胶质瘤干细胞（GSC）的存在，它具有取之不尽的自我更新能力， 增殖。由于GSCs具有较高的端粒酶水平，因此我建议通过抑制端粒酶来靶向GSCs 活性高于体细胞和其他非GSC肿瘤细胞。关于目标1，我将探讨GSC对以下问题的反应： 端粒酶抑制与三个独立的模型系统。我还会检测抗端粒酶抗体是否 在组合治疗方案中常规放射治疗和化学治疗。我以前的研究 显示抗端粒酶将通过ALT（端粒替代延长）导致耐药性 机制，因此在目标2中，我将产生和表征依赖于ALT机制的GSC，并将探索 靶向ALT的弱点以防止对抗端粒酶的抗性的可能性 疗法越来越多的证据表明，染色质重塑因子在调节细胞凋亡中起着重要作用。 因此，在目标3中，我将研究端粒酶+端粒染色质重塑的机制。 和ALT+胶质瘤干细胞。从这一目标中获得的信息将有助于我们理解ALT的性质 GSC背景下的机制，并提供新的治疗机会，以靶向ALT+ GSC。这 我所提议的研究将帮助我形成一个强大的研究计划，我将启动一个独立的教师队伍 学术/医学研究机构的职位。为此，我的近期目标是继续 我在小鼠遗传学、端粒生物学和干细胞生物学方面的技术能力得到了提高， 具有肿瘤基因组学、生物统计学和转化生物学方面的技能。就我的职业发展而言，我将 致力于提高我在管理实验室，指导博士后和学生，科学写作和 演讲，寻求合作，等等，因为这些技能对我来说都是必不可少的， 获得教职成为一名成功的私家侦探MD安德森癌症中心（MDACC）和罗纳德德皮纽 实验室为我实现这些目标提供了一个极好的培训环境。尽管德皮尼奥医生 虽然现在是MDACC的主席，但他仍然承诺会在我的培训和职业发展上投入2.5%的精力。我 我还成立了一个特别咨询委员会，成员包括黄绵枝博士、容伟钧博士、 和陈俊杰医生。他们不仅将为我的研究提供技术支持， 寻找教职并成为一名成功的独立调查员。在K99/R 00培训的帮助下 授予，我将有一个良好的开端，以实现我的长期目标，这是继续探索基本和 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 作为学术/医学研究机构的负责人， 通过与其他科学家、医生和制药公司合作，成为团队合作者。

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.