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: 8877657
• 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 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8877657
• 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; Health; 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; 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培训，随后被聘为斯坦福大学神经外科助理教授。我近期的职业目标包括建立一个致力于了解恶性胶质瘤生物学的实验室，并将这项工作转化为临床试验。在近期，在Albert Wong博士和神经外科系的指导和支持下，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询问和回答科学问题的能力，完善我的拨款写作技巧，并解决项目问题。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%的研究时间，以及启动资金和研究人员来执行拟议的项目。我的位置比我的导师Wong博士高出两层，毗邻神经外科实验室，这将有助于在资助期间积极指导和成长。王博士和我将至少每周开会讨论可能出现的任何问题。Wong博士在将项目转化为临床试验方面有着悠久的历史，并参与了许多临床试验。而且，为了补充我的导师和指导，我将充分利用斯坦福大学提供的丰富资源，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。我还将参加国家和国际会议，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与加里·斯坦伯格博士的实验室相邻。他是一个成功的外科医生科学家的典范，也是一个巨大的榜样，我可以向他寻求指导。Steinberg博士是神经外科系主任，也是斯坦福大学神经创新和转化神经科学研究所（SINTN）主任。他已经成功地建立了一个忙碌临床实践，以及运行一个大型的NIH资助的实验室研究植入干细胞治疗中风。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独立之路。该委员会包括加里斯坦伯格博士，基思布莱克博士-一个受人尊敬的外科医生科学家，Cedar Sinai医疗中心神经外科主席，脑肿瘤治疗和血脑屏障专家，Irv Weissman博士，他是斯坦福大学干细胞生物学和再生医学研究所所长，也是干细胞研究领域的领导者，在抗体方法方面拥有丰富的经验。癌症的治疗。我的研究项目源于我的实验室进行的初步数据，独立于我的导师，自2011年10月开始我的实验室。我的研究集中在酪蛋白激酶2（CK 2）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有关。有直接证据表明，催化亚基CK 2 α的表达或活性增强在胶质母细胞瘤（GBM）肿瘤发生中起重要作用。来自我实验室的数据表明，CK 2 α调节GBM癌症干细胞生长所必需的途径的新功能。本课题的主要目的是阐明CK 2 α在GBM肿瘤干细胞维持和生长中的作用，研究CK 2 α在GBM肿瘤发生中的活化机制，并利用颅内小鼠模型研究CK 2 α在GBM肿瘤干细胞中的靶向作用。我的假设是，CK 2 α通过调节Wingless/Int.（WNT）和Sonic Hedgehog（SHH）等信号级联反应在维持GBM癌症干细胞中发挥重要作用。因此，通过靶向CK 2 α，我希望阐明一种新的GBM治疗靶点，将消除促进GBM生长和形成的癌症干细胞。获得K 08资金对我作为独立临床研究员的发展至关重要，为我的研究计划提供了必要的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、教学方法和资源，以及理想的环境，让我成长为一名科学家，并发展成为一名独立的研究者。我的长期目标是成为斯坦福大学综合性脑肿瘤中心的领导者，在那里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公认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， 我受到启发，在这个最佳的环境中脱颖而出，拥有丰富的资源来实现我的目标，并荣幸地在这里开始我的职业生涯。