Microenvironmental Nutrient Availability and Immunomodulation in Lung Cancer Cel

肺癌细胞的微环境营养素利用率和免疫调节

• 批准号: 8744921
• 负责人: Teresa Whei-Mei Fan
• 金额: $ 27.33万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-19 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8744921
• 关键词: Affect; American; Anabolism; Behavior; Benign; Biochemical; Biochemical Pathway; Biochemistry; Cancerous; Cells; Cessation of life; Clinical; Colon Carcinoma; Data; Development; Early Diagnosis; Enzymes; Epithelial Cells; Event; Extracellular Matrix; Food Interactions; Genes; Glucans; Glucose; Glutaminase; Glutamine; Human; Hypoxia; Immune; Instruction; Knowledge; Lung; Lung Neoplasms; Malignant Neoplasms; Malignant neoplasm of lung; Malignant neoplasm of prostate; Maps; Medicine; Metabolic; Metabolism; Modification; Mus; Non-Small-Cell Lung Carcinoma; North America; Nutrient; Pathway interactions; Patients; Research; Resected; Stromal Cells; Structure of parenchyma of lung; System; Therapeutic; Tracer; arginase; base; cancer cell; cell motility; hyaluronan synthase 1; immunoregulation; improved; killings; macrophage; malignant breast neoplasm; metabolomics; mortality; novel; novel strategies; nutrient metabolism; outcome forecast; response; sensor; stable isotope; transcriptomics; tumor; tumor microenvironment; tumor xenograft

. PROJECT SUMMARY (See instructions); We propose a systems biochemical study of lung cancer (LC) cell nutrient metabolism of importance to LC development, survival and progression in the tumor microenvironment (TME). The primary approach is to utilize stable isotopic (13C and 15N) nutrient tracers in conjunction with stable isotope-resolved metabolomics (SIRM) and metabolomics-edited transcriptomic analysis (META) to discern key metabolic events in LC cells that govern their behavior and vulnerability in response to major TME factors such as hypoxia and nutrient deficiency. A central focus of this cell-based project is to understand the interaction of nutrient availability and hypoxia in modulating LC cell metabolism and how this may affect its ability to grow, survive and progress. This focus is in part motivated by our recent finding from the gene array data of paired cancerous and benign lung tissues resected from human patients regarding the dysregulations of key enzymes (e.g. arginase, glutaminase, hyaluronan synthase 2) involved in metabolism of glutamine and glucose. It is also driven by our recent discovery of arginase suppression in lung tumor xenograft and activation of Gin metabolism in murine macrophages by a natural immune activator, B-glucan. We will accomplish this with the following specific aims: SAI: SIRM profiling of lung cells for reconstructing biochemical pathways involved in utilization of glucose and glutamine. Biochemical pathways of these nutrients relevant to energy, anabolism, immunomodulatory sensors, and cell migration-related extracellular matrix factors will be mapped in LC cells harboring major driver gene anomalies, normal epithelial cells, and relevant stromal cells for comparison. SA2: Probe interactions of nutrient availability in combination with hypoxia. We will focus on 2 key questions: 1) How does Gin alleviate glucose demand by LC cells?; 2) Is Gin metabolism crucial to hypoxic LC cells?. SAS: Examine Arg metabolism in human tumor-associated macrophages as a function of Gin and Arg availability. Gin and Arg utilization pathways of relevance to immunomodulation in tumor-associated human macrophages will be probed in response to immune activator (B-glucans) and M2 to Ml polarization. The knowledge gained from this project will be used to help interpret data obtained from Projects 2 and 3.

。项目总结（见说明书）；