Targeting nutrient-sensing pathways in cancer

针对癌症中的营养感应途径

• 批准号: 9013361
• 负责人: Michael Block Lazarus
• 金额: $ 19.06万
• 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 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9013361
• 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; Development; Disease model; Doctor of Philosophy; Educational workshop; Employee Strikes; Energy Metabolism; Environment; Enzymes; Face; Faculty; Family; Genes; Glucose; Goals; Growth; Health; 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; Staging; Starvation; Stress; Structural Biochemistry; Structure; Techniques; Training; Transcript; Transition Career Development Award (K22); Translations; Universities; Work; 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; neoplastic cell; neuroblastoma cell; novel; novel strategies; novel therapeutics; nutrient deprivation; outcome forecast; professor; programs; response; 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 Kevan Shokat 教授实验室的博士后研究员。他在博士学位期间拥有结构生物学和生物化学方面的深厚背景，但在博士后和博士后期间一直寻求在蛋白质组学、细胞生物学和核糖体分析方面获得更多经验。 K22 奖励期结束时，Lazarus 博士将拥有一套全面且令人兴奋的技能，他将能够利用这些技能开展与营养信号相关的癌症生物学的前沿研究。他的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、这些机制在癌症中如何改变，以及最终如何将它们用于新的治疗策略。该提案围绕两种不寻常的酶来调节细胞一种是一种称为延伸因子 2 激酶 (eEF2K) 的蛋白质，其功能是调节细胞内的翻译以应对营养缺乏。该激酶属于一种称为 α 激酶的非典型激酶家族，它具有非规范序列。并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产生抵抗力而对肿瘤存活很重要，但其作用机制尚不清楚。在这项提案中，Lazarus 博士试图识别 eEF2K 的新底物，并了解翻译调节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，将对翻译调节产生新的理解。另一种酶是一种名为 ULK1 的激酶，它会在细胞中启动自噬，当营养物质不足时，细胞可以通过该过程降解细胞成分以获取能量。Lazarus 博士将开发第一种 ULK1 细胞抑制剂并探测该激酶。通过研究这两种酶的工具，拉扎勒斯博士将建立一个可靠的计划来研究癌症中的营养信号传导。拉扎勒斯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开发新技能。他目前的导师是 Kevan Shokat，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揭示癌症复杂信号通路方面的世界领先者。在 Shokat 教授的实验室，Michael 将开发了解 eEF2K 和 ULK1 的工具。在 Shokat 教授的实验室中，Michael 一直在学习底物识别技术以及制造新抑制剂的有机合成技术。此外，Lazarus 博士还接受了两位顶尖科学家的培训。 William Weiss 教授是加州大学旧金山分校 Shokat 教授的长期合作者，他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 在激酶所在的癌细胞系中的作用。通过学习如何在相关细胞系中研究激酶及其底物，Lazarus 博士获得了基础细胞生物学技术方面的经验，并学习了 eEF2K 在相关疾病模型中发挥作用的新途径，这些新途径将成为相关疾病模型的一部分。 Lazarus 博士的独立研究也受益于与 Davide Ruggero 教授的合作，Davide Ruggero 教授是翻译调控和核糖体分析方面的领先专家。 Lazarus 博士将学习核糖体分析和翻译生化分析技术。Weiss 教授和 Ruggero 教授均位于 UCSF 校园，并经常与 Lazarus 博士和 Shokat 教授会面，为这一合作性多学科项目提供指导。 Lazarus 博士一直与 Weiss 教授和 Ruggero 教授实验室的成员密切合作，学习新技术并回答有关他的项目的问题，UCSF 丰富的环境将成为 Dr. Lazarus 的重要组成部分。拉扎勒斯作为一名科学家接受过培训，因为他的导师与加州大学旧金山分校的数十名具有不同专业知识的教员持续合作，这些更非正式的互动和建议将成为宝贵的资源。此外，拉扎勒斯博士将参加加州大学旧金山分校的重要研讨会，这将是对他的补充。总之，由于 UCSF 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。