Studying a novel regulator of GBM tumorigeneis: the role of CK2alpha in maintaini

研究 GBM 致瘤的新型调节因子：CK2α 在维持性中的作用

• 批准号: 8618186
• 负责人: Gordon Li
• 金额: $ 17.97万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-30 至 2018-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8618186
• 关键词: American Association of Cancer Research; Antibodies; Biological Assay; Biology; Blood - brain barrier anatomy; Brain Neoplasms; Cancer Biology; Catalytic Domain; Cell Maintenance; Cell Survival; Cells; Cellular Assay; Cessation of life; Chairperson; Clinical; Clinical Trials; Collaborations; Data; Development; Diagnosis; Disease; Educational process of instructing; Environment; Epidermal Growth Factor Receptor; Erinaceidae; Exhibits; Floor; Fluorescent in Situ Hybridization; Funding; GLI gene; Gene Amplification; Genes; Glioblastoma; Goals; Grant; Growth; Half-Life; In Vitro; Injection of therapeutic agent; Institutes; International; Ionizing radiation; Knowledge; Laboratories; Laboratory Study; Lead; Learning; Life; Location; Malignant Glioma; Malignant Neoplasms; Malignant neoplasm of brain; Medical center; Mentors; Mentorship; Methods; Monitor; Oncology Group; Operative Surgical Procedures; Pathway interactions; Patients; Pharmaceutical Preparations; Phenotype; Play; Protein-Serine-Threonine Kinases; Proteins; Radiosurgery; Recording of previous events; Refractory; Regenerative Medicine; Regulation; Research; Research Personnel; Research Project Grants; Residencies; Resources; Role; Running; Scientist; Signal Pathway; Signal Transduction; Societies; Solid Neoplasm; Stem Cell Research; Stem cells; Stroke; Structure; Surgeon; System; Techniques; Therapeutic; Therapeutic Clinical Trial; Three-Dimensional Imaging; Time; Translating; United States National Institutes of Health; Universities; Work; Writing; base; cancer stem cell; cancer therapy; career; casein kinase II; cell growth; chemotherapy; clinical practice; design; epidermal growth factor receptor VIII; experience; implantation; improved; in vivo; inhibitor/antagonist; innovation; meetings; mouse model; nerve stem cell; nestin protein; neuro-oncology; neurosurgery; novel; outcome forecast; overexpression; professor; programs; public health relevance; role model; self-renewal; skills; small hairpin RNA; small molecule; stem; stem cell biology; symposium; therapeutic target; traditional therapy; transcription factor; translational neuroscience; tumor; tumor growth; tumorigenesis; tumorigenic

DESCRIPTION (provided by applicant): I completed my neurosurgery residency in June of 2011 and was subsequently hired as Assistant Professor of Neurosurgery at Stanford University. My immediate career goals include building a laboratory dedicated to understanding the biology of malignant gliomas and translating this work to clinical trials. In the near term, wih the mentorship and support of Dr. Albert Wong and the Department of Neurosurgery, I will advance my knowledge of laboratory techniques, learn to manage a laboratory, teach and mentor in a structured environment, further develop my ability to critically ask and answer scientific questions, refine my grant writing skills, and troubleshoot projects. My goal is to transition to independence by the conclusion of this project. I have received significant support from Stanford, including laboratory space and 50% dedicated time towards research, as well as startup funds and research personnel to carry out the proposed project. My location two floors above my mentor, Dr. Wong, and next door to the Department of Neurosurgery laboratories will facilitate active mentoring and growth during the grant period. Dr. Wong and I will meet at least weekly to discuss any questions that may arise. Dr. Wong has a long history of translating projects to clinical trials and has been involved in many clinical trials. Moreover, to supplement my mentorship and guidance, I will take full advantage of the rich resources available at Stanford University, including conferences, forums, programs and classes designed to help young investigators develop and grow. I will also attend national and international meetings, including the Society for Neuro-Oncology, American Association for Cancer Research, Cold Spring Harbor Laboratory on Cancer Biology and Therapeutics, and Keystone Symposia meetings. Importantly, my laboratory and offices are adjacent to the laboratory of Dr. Gary Steinberg. He is an exemplary example of a successful surgeon-scientist and is a tremendous role model to whom I can look for guidance. Dr. Steinberg is the Chairman of the Department of Neurosurgery as well as Director of the Stanford Institute for Neuro- Innovation and Translational Neurosciences (SINTN). He has successfully built a busy clinical practice as well as run a large NIH-funded laboratory studying the implantation of stem cells for the treatment of stroke. I will meet with him on a monthly basis. I have additionally organized an independent committee to oversee my development and path towards independence. This committee includes Dr. Gary Steinberg, Dr. Keith Black- a respected surgeon-scientist, Chairman of Neurosurgery at Cedar Sinai Medical Center and an expert on brain tumor therapies and the blood-brain barrier-and Dr. Irv Weissman-the Director of the Institute for Stem Cell Biology and Regenerative Medicine at Stanford University and a leader in the field of stem cell research who has vast experience with antibody approaches for the treatment of cancer. My research project stems from preliminary data performed in my laboratory, independent of my mentor, since commencing my laboratory in October of 2011. My studies focus on the role of casein kinase 2 (CK2), a highly conserved pleiotropic serine/threonine kinase that has been associated with cell survival in many cancers. There is direct evidence demonstrating that enhanced expression or activity of the catalytic subunit CK2α plays an important role in glioblastoma (GBM) tumor genesis. Data from my laboratory indicate a novel function in which CK2α regulates pathways necessary for GBM cancer stem cell growth. The goals of my proposed research project are to elucidate the role of CK2α in GBM cancer stem cell maintenance and growth, to study the mechanism of activation of CK2α in GBM tumor genesis, and to develop strategies to target CK2α in GBM cancer stem cells using an intracranial mouse model. My hypothesis is that CK2α is important in maintaining GBM cancer stem cells through the regulation of signaling cascades such as Wingless/Int. (WNT) and Sonic Hedgehog (SHH). Therefore, by targeting CK2α I hope to elucidate a novel GBM therapeutic target that will eliminate the cancer stem cells that promote growth and formation of GBMs. Obtaining K08 funding is crucial to my development as an independent clinician-investigator, providing the necessary protected time and structured mentoring required to develop my research program. Stanford has equipped me with all the necessary mentoring, didactics, and resources as well as the ideal environment to grow as a scientist and to evolve into an independent investigator. My long term goals are to be a leader in a comprehensive brain tumor center at Stanford where discoveries in the laboratory translate to clinical therapeutics trials, and to join Stanford's nationally recognized surgical neuro-oncology group. Supported by a long history of collaboration with other clinical and scientific departments, I am inspired to excel in this optimal environment, replete with rich resources to achieve my goals, and honored to begin my career here.

描述（由申请人提供）：我于 2011 年 6 月完成了神经外科住院医师实习，随后被斯坦福大学聘为神经外科助理教授。我的近期职业目标包括建立一个实验室，致力于了解恶性胶质瘤的生物学，并将这项工作转化为临床试验。短期内，在黄克强医生和神经外科的指导和支持下，我将提高我的实验室技术知识，学习管理实验室，在结构化环境中教学和指导，进一步发展我批判性地提出和回答科学问题的能力，提高我的资助写作技巧，以及解决项目问题。我的目标是在这个项目结束时过渡到独立。我得到了斯坦福大学的大力支持，包括实验室空间和 50% 的专门研究时间，以及启动资金和研究人员来开展拟议的项目。我的位置比我的导师黄博士高两层，毗邻神经外科实验室，将有助于在资助期间积极指导和成长。黄博士和我至少每周会面一次，讨论可能出现的任何问题。黄博士在将项目转化为临床试验方面拥有悠久的历史，并参与了许多临床试验。此外，为了补充我的指导和指导，我将充分利用斯坦福大学丰富的资源，包括旨在帮助年轻研究人员发展和成长的会议、论坛、项目和课程。我还将参加国内和国际会议，包括神经肿瘤学会、美国癌症研究协会、冷泉港癌症生物学和治疗实验室以及 Keystone 研讨会。重要的是，我的实验室和办公室毗邻加里·斯坦伯格博士的实验室。他是成功外科医生科学家的典范，也是我可以寻求指导的伟大榜样。 Steinberg 博士是神经外科系主任以及斯坦福神经创新和转化神经科学研究所 (SINTN) 所长。他成功地建立了繁忙的临床实践，并运营着一个由美国国立卫生研究院 (NIH) 资助的大型实验室，研究干细胞植入治疗中风。我将每月与他会面。我还组织了一个独立委员会来监督我的发展和走向独立的道路。该委员会成员包括加里·斯坦伯格 (Gary Steinberg) 博士、受人尊敬的外科医生科学家、雪松西奈医学中心神经外科主席、脑肿瘤治疗和血脑屏障专家基思·布莱克 (Keith Black) 博士，以及斯坦福大学干细胞生物学和再生医学研究所所长、干细胞研究领域的领导者、在治疗癌症的抗体方法方面拥有丰富经验的欧文·韦斯曼 (Irv Weissman) 博士。我的研究项目源于自 2011 年 10 月开始我的实验室以来在我的实验室独立于我的导师进行的初步数据。我的研究重点是酪蛋白激酶 2 (CK2) 的作用，这是一种高度保守的多效性丝氨酸/苏氨酸激酶，与许多癌症中的细胞存活相关。有直接证据表明催化亚基 CK2α 的表达或活性增强在胶质母细胞瘤 (GBM) 肿瘤发生中发挥重要作用。我实验室的数据表明 CK2α 具有调节 GBM 癌症干细胞生长所需途径的新功能。我提出的研究项目的目标是阐明 CK2α 在 GBM 癌症干细胞维持和生长中的作用，研究 CK2α 在 GBM 肿瘤发生中的激活机制，并开发使用颅内小鼠模型靶向 GBM 癌症干细胞中 CK2α 的策略。我的假设是，CK2α 通过调节信号级联（例如 Wingless/Int）对于维持 GBM 癌症干细胞非常重要。 （WNT）和索尼克刺猬（SHH）。因此，通过靶向 CK2α，我希望阐明一种新的 GBM 治疗靶点，消除促进 GBM 生长和形成的癌症干细胞。获得 K08 资金对于我作为独立临床医生研究员的发展至关重要，为我提供开发研究项目所需的必要保护时间和结构化指导。斯坦福大学为我提供了所有必要的指导、教学和资源，以及成长为一名科学家并发展成为一名独立研究者的理想环境。我的长期目标是成为斯坦福大学综合脑肿瘤中心的领导者，将实验室的发现转化为临床治疗试验，并加入斯坦福大学全国认可的外科神经肿瘤学小组。在与其他临床和科学部门长期合作的支持下， 在这个理想的环境中，我受到激励，能够脱颖而出，拥有丰富的资源来实现我的目标，并很荣幸在这里开始我的职业生涯。