The proposed study is to explore novel therapeutic opportunities to cure malignant gliomas by perturbingtelomere maintenance mechanisms in glioma stem cells. Malignant gliomas are highly resistant to treatmentlargely due to the existence of glioma stem cells (GSCs), which possess inexhaustible ability to self-renew andproliferate. I propose to target GSCs by inhibiting telomerase because GSCs have higher level of telomeraseactivity than somatic cells and other non-GSC tumor cells. With Aim 1, I will explore GSCs' response totelomerase inhibition with three independent model systems. I will also test whether anti-telomerase sensitizesconventional radiation therapy and chemotherapy in combinatorial therapy regimens. My previous studyshowed 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 explorethe possibility to target the weakness of ALT in order to prevent the resistance in response to anti-telomerasetherapy. More evidence is pointing to the important function of chromatin remodeling factors in the regulation oftelomeres, 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 ALTmechanisms in the GSC context and provide new therapeutic opportunities to target ALT+ GSCs. Thisproposed study will help me to form a strong research program, with which I will launch an independent facultyposition in an academic/medical research institution. To that end, my immediate goals are to continuesharpening my technical skills in mouse genetics, telomere biology and stem cell biology and expanding myskills in oncogenomics, biostatistics and translational biology. In terms of my career development, I will bedevoted to improve my skills on managing lab, mentoring postdocs and students, scientific writing andpresentation, and seeking for collaborations, among others, because these skills are all essential for me toland a faculty position and succeed as a PI. MD Anderson Cancer Center (MDACC) and the Ronald DePinholaboratory provide an excellent training environment for me to achieve these goals. Even though Dr. DePinhois President of MDACC now, he still promises to devote 2.5% effort to my training and career development. Ihave also formed an extraordinary advisory committee composed of Dr. Mien-Chie Huang, Dr. Wai-Kwan Yungand Dr. Junjie Chen. They will not only provide me technical support for my proposed study, but also guide meto look for a faculty position and succeed as an independent investigator. With the help of K99/R00 traininggrant, I will have a good start to achieve my long term goals, which are to continue exploring basic andtranslational problems in cancer biology, including telomere biology and cancer stem cell biology, as a labhead in an academic/medical research institute and to contribute in developing novel cancer therapies as ateam player by collaborating with other scientists, physicians and pharmaceutical companies.