Targeting nutrient-sensing pathways in cancer

针对癌症中的营养感应途径

• 批准号: 9320652
• 负责人: Michael Block Lazarus
• 金额: $ 19.14万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-01 至 2017-09-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9320652
• 关键词: Affect; Autophagocytosis; Award; Biochemical; Biology; California; Cancer Biology; Cancer cell line; Cell Line; Cell Survival; Cell physiology; Cells; Cellular biology; Chemicals; Collaborations; Complex; Consumption; Crystallization; Development; Disease model; Doctor of Philosophy; Educational workshop; Employee Strikes; Energy Metabolism; Environment; Enzymes; Face; Faculty; Family; Genes; Glucose; Goals; Growth; Homeostasis; K22 Award; Laboratories; Learning; Link; Malignant Neoplasms; Mediating; Mediator of activation protein; Mentors; Metabolic stress; Metabolism; Modeling; Monitor; Mutate; Neuroblastoma; Normal Cell; Nutrient; Organelles; Organic Synthesis; Pathway interactions; Patients; Peptide Elongation Factor 2; Phosphoric Monoester Hydrolases; Phosphorylation; Phosphorylation Site; Phosphotransferases; Positioning Attribute; Process; Production; Protein Kinase; Protein Phosphatase 2A Regulatory Subunit PR53; Proteins; Proteomics; Regulation; Research; Research Personnel; Research Proposals; Resistance; Resources; Role; San Francisco; Scientist; Signal Pathway; Signal Transduction; Solid; Source; Starvation; Stress; Structural Biochemistry; Structure; Techniques; Training; Transcript; Transition Career Development Award (K22); Translations; Universities; angiogenesis; calmodulin-dependent protein kinase III; cancer cell; cancer therapy; career; cell growth; chemotherapy; collaborative environment; cost; design; detection of nutrient; experience; inhibitor/antagonist; interest; kinase inhibitor; laboratory experience; meetings; member; multidisciplinary; neoplastic cell; neuroblastoma cell; novel; novel strategies; novel therapeutics; nutrient deprivation; outcome forecast; professor; programs; public health relevance; response; ribosome profiling; skills; structural biology; therapeutic target; tool; tool development; tumor; tumor progression; tumorigenesis

 DESCRIPTION (provided by applicant): The candidate for this NCI Transition Career Development Award (K22) is Michael Lazarus, Ph.D., a postdoctoral researcher in the lab of Professor Kevan Shokat at the University of California, San Francisco. Dr. Lazarus has a strong background in structural biology and biochemistry from his Ph.D. but has sought to gain additional experience in proteomics, cell biology, and ribosomal profiling in his postdoctoral and K22 award period. At the end of the award period, Dr. Lazarus will have a well-rounded and exciting set of skills with which he will be able to carry out cutting edge research in cancer biology related to nutrient signaling. His long-term goal is to have his own lab at a research university focused on studying the mechanisms by which cells respond to nutrient changes, how these mechanisms can be altered in cancer, and finally how they can be exploited for novel therapeutic strategies. The focus of this research proposal centers around two unusual enzymes that regulate cellular responses to starvation. One is a protein called elongation factor-2 kinase (eEF2K) which functions to regulate translation in cells in response to nutrient deprivation. The kinase belongs to an atypical family of kinases called alpha kinases; it has a non-canonical sequence and has not benefitted from the recent development of tools used to study conventional protein kinases. eEF2K has been shown to be important for tumor survival by rendering cancer cells resistant to nutrient changes, but the mechanisms by which it does this are unclear. In this proposal, Dr. Lazarus seeks to identify novel substrates of eEF2K and understand how regulation of translation allows cancer cells to adapt to nutrient deprivation. By determining which transcripts are most affected by eEF2K activity, a new understanding of translation regulation will emerge. The other enzyme is a kinase called ULK1 that initiates autophagy in cells, a process whereby cells can degrade cellular components for energy when nutrients are low. Dr. Lazarus will develop the first cellular inhibitors of ULK1 and probe the kinase's function in cancer. By developing tools to study these two enzymes, Dr. Lazarus will have a solid program in studying nutrient signaling in cancer. Dr. Lazarus has assembled an impressive team of scientists to help him tackle these challenging questions and learn new skills to complete his training and transition into an independent investigator. His current mentor is Kevan Shokat, a world leader in indentifying substrates of kinases, developing selective kinase inhibitors, and using chemical tools to unravel complex signaling pathways in cancer. Dr. Lazarus has been working in Professor Shokat's laboratory, and will develop tools to understand eEF2K and ULK1. In Professor Shokat's lab, Michael has been learning techniques of substrate identification as well as organic synthesis for making new inhibitors. In addition, Dr Lazarus has been receiving training from two leading scientists who are longtime collaborators with Professor Shokat at UCSF. Professor William Weiss is a world expert on neuroblastoma models and will train Dr. Lazarus to investigate the role of eEF2K in cancer cell lines where the kinase has been strongly linked to patient prognosis. By learning how to investigate the kinase and its substrates in relevant cell lines, Dr. Lazarus is gaining experience in fundamental cell biology techniques as well as learning new avenues of eEF2K function in relevant disease models that will become part of Dr. Lazarus's independent research. Dr. Lazarus is also benefiting from working with Professor Davide Ruggero, who is a leading expert on translation regulation and ribosomal profiling. By working with Professor Ruggero, Dr. Lazarus will learn techniques in ribosomal profiling and biochemical analysis of translation. Both Professor Weiss and Professor Ruggero are located at the UCSF campus and have been meeting frequently with Dr. Lazarus and Professor Shokat to provide guidance on this collaborative and multi-disciplinary project. Dr. Lazarus has been working closely with members of Professor Weiss's and Professor Ruggero's labs to learn new techniques and answer questions about his project. This rich environment at UCSF will be a key component of Dr. Lazarus's training as a scientist, since his mentor has ongoing collaborations with dozens of faculty members at UCSF with different expertises. These more informal interactions and advice will be an invaluable resource. In addition, Dr. Lazarus will attend key workshops UCSF that will supplement his laboratory training with professional development. In summary, because of this rigorous training plan and collaborative environment at UCSF, Dr. Lazarus will be uniquely positioned to make new discoveries about eEF2K and ULK1 and also be ready for a strong independent academic career.

 描述(由申请人提供)：NCI过渡职业发展奖(K22)的候选人是Michael Lazarus博士，他是加州大学旧金山分校Kevin an Shokat教授实验室的博士后研究员。Lazarus博士在他的博士学位中拥有强大的结构生物学和生物化学背景，但在他的博士后和K22获奖期间，他一直在寻求在蛋白质组学、细胞生物学和核糖体图谱方面获得更多经验。在获奖期结束时，Lazarus博士将拥有一套全面而令人兴奋的技能，他将能够开展与营养信号相关的癌症生物学的尖端研究。他的长期目标是在一所研究型大学建立自己的实验室，专注于研究细胞对营养变化的反应机制，这些机制如何在癌症中改变，以及如何利用这些机制来开发新的治疗策略。这项研究计划的重点是两种不寻常的酶，它们调节细胞对饥饿的反应。一种是一种名为延长因子-2激酶(EEF2K)的蛋白质，它的功能是调节细胞内的翻译，以应对营养缺乏。该激酶属于一个非典型的被称为阿尔法激酶的家族；它有一个非规范的序列，并且没有受益于最近用于研究传统蛋白激酶的工具的发展。EEF2K已被证明通过使癌细胞对营养变化具有抵抗力而对肿瘤生存具有重要作用，但其机制尚不清楚。在这项研究中，Lazarus博士试图确定eEF2K的新底物，并了解翻译调控如何使癌细胞适应营养缺乏。通过确定哪些转录本受eEF2K活性影响最大，将出现对翻译调控的新理解。另一种酶是一种名为ULK1的激酶，它在细胞中启动自噬，当营养物质不足时，细胞可以通过这个过程降解细胞成分以获得能量。Lazarus博士将开发ULK1的第一个细胞抑制剂，并探索该激酶在癌症中的功能。通过开发研究这两种酶的工具，拉撒路博士将在研究癌症中的营养信号方面有一个坚实的计划。拉撒路博士组建了一支令人印象深刻的科学家团队，帮助他解决这些具有挑战性的问题，并学习新的技能，以完成培训并过渡为一名独立研究人员。他目前的导师是凯文·肖卡特，他是鉴定激酶底物、开发选择性激酶抑制剂以及使用化学工具解开癌症复杂信号通路方面的世界领先者。Lazarus博士一直在Shokat教授的实验室工作，并将开发工具来理解eEF2K和ULK1。在肖卡特教授的实验室里，迈克尔一直在学习底物识别和有机合成技术，以制造新的抑制剂。此外，Lazarus博士一直在接受两位顶尖科学家的培训，他们是加州大学旧金山分校Shokat教授的长期合作伙伴。William Weiss教授是神经母细胞瘤模型方面的世界专家，他将培训Lazarus博士研究eEF2K在癌细胞系中的作用，在癌细胞系中，该激酶与患者的预后密切相关。通过学习如何在相关细胞系中研究激酶及其底物，Lazarus博士正在获得基础细胞生物学技术方面的经验，并在相关疾病模型中了解eEF2K功能的新途径，这将成为Lazarus博士独立研究的一部分。拉撒路博士还受益于与戴维德·鲁格罗教授的合作，鲁杰罗教授是翻译调控和核糖体图谱方面的领先专家。通过与鲁格罗教授的合作，拉撒路博士将学习核糖体图谱和翻译生化分析方面的技术。Weiss教授和Ruggero教授都位于加州大学旧金山分校，并经常与Lazarus博士和Shokat教授会面，为这个合作和多学科的项目提供指导。Lazarus博士一直在与Weiss教授和Ruggero教授的实验室成员密切合作，学习新技术并回答有关他的项目的问题。加州大学旧金山分校的这种丰富的环境将是拉撒路博士作为一名科学家进行培训的关键组成部分，因为他的导师与加州大学旧金山分校数十名拥有不同专业知识的教职员工持续合作。这些更非正式的互动和建议将是一种宝贵的资源。此外，Lazarus博士将参加加州大学旧金山分校的关键研讨会，这些研讨会将补充他的实验室培训和专业发展。总之，由于加州大学旧金山分校严格的培训计划和协作环境，Lazarus博士将处于独特的地位，能够对eEF2K和ULK1做出新的发现，并为强大的独立学术生涯做好准备。