Investigating the Role of Metabolic Reprogramming in Cancer Cell Death Sensitivity

研究代谢重编程在癌细胞死亡敏感性中的作用

基本信息

批准号：
10153740
负责人：
Amy Tarangelo
金额：
$ 9.21万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-04-03 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10153740
关键词：
Address Affect Amino Acids Antioxidants Attention Biochemical Biochemical Pathway Biological Assay Biological Models CDKN1A gene Cancer Biology Cancer Cell Growth Cancer Model Cell Culture Techniques Cell Death Cell model Cells Cellular Metabolic Process Cellular Stress Chemicals Complex Consumption Cysteine Dependence Development Doctor of Philosophy Drug Tolerance Environment Enzymes Excretory function Exposure to Folic Acid Genes Genetic Genetic Transcription Glutathione Glutathione Disulfide Glutathione Metabolism Pathway Goals Growth Head Human In Vitro Iron Laboratory Research Laboratory Study Link Lipids Malignant Neoplasms Mediating Metabolic Metabolic stress Metabolism Methotrexate Modeling Mus Mutation Natural regeneration Oncogenes Oncogenic Pathway interactions Phenotype Physiological Positioning Attribute Predisposition Reactive Oxygen Species Reduced Glutathione Research Research Personnel Research Project Grants Resistance Role Scientist Secure Serum System TP53 gene Technical Expertise Testing Therapeutic Training Tumor Suppressor Genes Work Xenograft Model anticancer research cancer cell cancer survival cancer therapy chemotherapy deprivation design drug sensitivity experience experimental study fibrosarcoma improved in vivo lipid metabolism metabolic abnormality assessment neoplastic cell novel novel therapeutic intervention oxidation post-doctoral training pre-doctoral skills therapeutic candidate therapeutic target therapy development tissue culture tool tumor tumor metabolism tumor progression

项目摘要

ABSTRACT Alterations in the metabolism of cancer cells can directly promote growth and survival and create metabolic dependencies. Targeting these metabolic dependencies is an attractive strategy for designing novel anti-cancer therapies. The development of these treatments is hindered by a major gap in our understanding of how changes in cancer cell metabolism, and in particular lipid metabolism, alter sensitivity to cell death induced by chemotherapy. My goal is to mechanistically define the links between cancer-associated mutations, metabolic lipid reprogramming, and sensitivity to cell death. F99 Training: During my dissertation research, I investigated the genetic and metabolic factors mediating cancer cell sensitivity to ferroptosis, a form of non-apoptotic cell death that occurs due to metabolic stress. Ferroptosis occurs when cells are deprived of the essential intracellular antioxidant, glutathione, leading to the toxic, iron-dependent accumulation of lipid reactive oxygen species (ROS). I discovered that the canonical tumor suppressor p53 and its downstream transcriptional target CDKN1A (encoding p21), suppress ferroptosis by reprogramming glutathione metabolism and decreasing the accumulation of lipid ROS. From this work it remains unclear how the p53-p21 pathway reprograms glutathione metabolism. I hypothesize that the p53-p21 pathway promotes the regeneration of reduced glutathione from oxidized glutathione to block lipid ROS accumulation. I will test this hypothesis in vivo and in vitro using genetic and chemical tools, metabolic tracing analysis, and mouse cancer models. This training will allow me to develop the skills and experience necessary to secure and succeed in a postdoctoral position at a top laboratory studying cancer metabolism. K00 Training: Alterations in lipid metabolism are common in cancer and may directly facilitate growth and survival. How changes in lipid metabolism impact cancer cell sensitivity to chemotherapy- induced cell death is not well understood. A major challenge in answering this question is that lipid metabolism is highly responsive to environmental conditions, and in vitro tissue culture systems poorly recapitulate the specific lipid metabolic environment experienced by cancer cells exposed to human serum. During my postdoctoral training, I will address this critical problem by developing new tools to more closely mimic the in vivo lipid metabolic environment in cell culture. Using these tools, I will determine how reprogramming of lipid metabolism alters cancer cell sensitivity to chemotherapy-induced cell death using large-scale genetic and chemical approaches. The training of the K00 will enable me to gain the technical and professional skills necessary to achieve my long-term goal of becoming an independent cancer investigator.

抽象的癌细胞代谢的改变可以直接促进生长和生存，并创造代谢依赖性。针对这些代谢依赖性是设计新型反癌的有吸引力的策略疗法。这些治疗的发展受到我们对变化方式的理解的主要差距的阻碍在癌细胞代谢，尤其是脂质代谢中，改变了对细胞死亡的敏感性化学疗法。我的目标是机械地定义与癌症相关突变，代谢之间的联系脂质重编程和对细胞死亡的敏感性。 F99培训：在论文研究中，我调查了介导癌细胞敏感性铁凋亡的遗传和代谢因子，这是一种非凋亡细胞的形式由于代谢压力而导致的死亡。当细胞被剥夺了必需的细胞内时，会发生铁铁作用抗氧化剂，谷胱甘肽，导致脂质活性氧的有毒，依赖铁的积累（ROS）。我发现规范肿瘤抑制p53及其下游转录靶CDKN1A （编码P21），通过重编程谷胱甘肽代谢并减少抑制铁氧作用脂质ROS的积累。从这项工作中，尚不清楚p53-P21途径如何重新编程谷胱甘肽代谢。我假设p53-p21途径促进了从氧化的谷胱甘肽以阻断脂质ROS的积累。我将使用遗传在体内和体外检验该假设以及化学工具，代谢跟踪分析和小鼠癌模型。这种培训将使我得以发展在顶级实验室学习的博士后职位上确保并取得成功所必需的技能和经验癌症代谢。 K00训练：脂质代谢的改变在癌症中很常见，可能直接促进生长和生存。脂质代谢的变化如何影响癌细胞对化学疗法的敏感性 - 诱发的细胞死亡尚不清楚。回答这个问题的主要挑战是脂质代谢对环境条件的反应很高，体外组织培养系统的概括很差暴露于人血清的癌细胞经历的特定脂质代谢环境。在我期间博士后培训，我将通过开发新工具来更加模仿体内来解决这个关键问题细胞培养中的脂质代谢环境。使用这些工具，我将确定如何重新编程脂质代谢使用大规模遗传和化学方法。 K00的培训将使我能够获得技术和专业技能要实现成为独立癌症研究者的长期目标所必需的。