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（由适用提供）：该NCI过渡职业发展奖（K22）的候选人是迈克尔·拉撒路（K22），他是加利福尼亚大学旧金山大学凯文·霍卡特（Kevan Shokat）教授的博士后研究员。 Lazarus博士在博士学位上具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奖项期间，遭受了在蛋白质组学，细胞生物学和核糖体分析方面的额外经验。在奖励期结束时，Lazarus博士将拥有一套全面且令人兴奋的技能，他将能够在与营养信号有关的癌症生物学方面进行尖端研究。他的长期目标是在一所研究大学拥有自己的实验室，专注于研究细胞对养分变化的反应，如何改变癌症的机制以及最终如何探索新理论策略的机制。该研究提案的重点集中在两个调节细胞对饥饿反应的异常酶周围。一种是一种称为伸长因子-2激酶（EEF2K）的蛋白质，该蛋白质可响应营养剥夺而调节细胞中的翻译。激酶属于一个非典型的激酶家族，称为α激酶。它具有非典型序列，并未从最近的发展中受益。用于研究常规蛋白激酶的工具。 EEF2K已被证明通过使癌细胞具有抵抗营养变化的癌细胞来重要，但是这样做的机制尚不清楚。在该提案中，Lazarus博士试图鉴定EEF2K的新底物，并了解翻译的调节如何使癌细胞适应营养剥夺。通过确定哪些成绩单受EEF2K活动影响最大，将出现对翻译调节的新理解。另一种酶是一种称为ULK1的激酶，它在细胞中启动自噬，在养分低时，细胞可以降解细胞成分的能量。 Lazarus博士将开发ULK1的第一个细胞抑制剂，并探测激酶在癌症中的功能。通过开发研究这两种酶的工具，Lazarus博士将在研究癌症中的营养信号传导方面具有坚实的计划。拉撒路博士召集了一支令人印象深刻的科学家团队，以帮助他解决这些挑战问题，并学习新技能，以完成他的培训和过渡到独立研究者。他目前的导师是凯文·索卡特（Kevan Shokat），他是激酶缩进底物，开发选择性激酶抑制剂的世界领导者，并使用化学工具来揭示癌症中复杂的信号通路。 Lazarus博士一直在Shokat教授的实验室工作，并将开发了解EEF2K和ULK1的工具。在Shokat教授的实验室中，迈克尔一直在学习底物识别的技术以及制造新抑制剂的有机合成。此外，Lazarus博士一直接受两位主要科学家的培训，他们是UCSF与Shokat教授的长期合作者。威廉·魏斯（William Weiss）教授是神经母细胞瘤模型的世界专家，将培训拉扎鲁斯博士，研究eef2k在激酶与患者预后密切相关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博士在基本细胞生物学技术方面获得了经验，并且在相关疾病模型中学习EEF2K的新途径，这些途径将成为Lazarus博士独立研究的一部分。 Lazarus博士还受益于与戴维德·鲁格罗（Davide Ruggero）教授合作，后者是翻译法规和核糖体分析的主要专家。通过与Ruggero教授合作，Lazarus博士将学习核糖体分析和翻译生化分析的技术。 Weiss教授和Ruggero教授都位于UCSF校园，并经常与Lazarus博士和Shokat教授会面，以提供有关此协作和多学科项目的指导。 Lazarus博士一直与Weiss教授和Ruggero教授的实验室的成员紧密合作，以学习新技术并回答有关其项目的问题。 UCSF的这种丰富的环境将是Lazarus博士作为科学家培训的关键组成部分，因为他的心理与UCSF的数十名教职员工与不同的专家进行了持续的合作。这些更非正式的互动和建议将是宝贵的资源。此外，Lazarus博士将参加主要研讨会UCSF，该研讨会将为他的实验室培训补充专业发展。总而言之，由于UCSF的这项严格的培训计划和协作环境，Lazarus博士将有独特的位置，可以对EEF2K和ULK1进行新的发现，并为实现强大的独立学术生涯做好准备。