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.

。项目摘要（请参阅说明）； 我们提出了一项对肺癌（LC）细胞营养代谢对LC发育，生存和进展重要性的系统生化研究。主要的方法是利用稳定的同位素（13C和15N）营养示踪剂与稳定的同位素分辨的代谢组学（SIRM）和代谢组学的转录组分析（META），以辨别出对主要症状和诸如主要tmoxia的响应响应的LC细胞中的关键代谢事件，例如，诸如主要的TME和弱点。该基于细胞的项目的一个主要重点是了解调节LC细胞代谢中养分的可用性和缺氧的相互作用，以及这如何影响其成长，生存和进步的能力。这种重点部分是由于我们最近从人类患者的基因阵列数据数据中的基因阵列数据数据中的基因阵列数据（例如，精氨酸酶，谷氨酰胺酶，透明质酸合成酶2）从人类患者中切除的基因阵列数据，涉及谷氨酰胺和糖糖的代谢失调。它也是由我们最近发现的肺肿瘤异种移植中精氨酸酶抑制作用的驱动的，以及通过天然免疫激活剂B-葡聚糖在鼠巨噬细胞中杜松子酒代谢的激活。我们将以以下特定目的来实现这一目标：SAI：肺细胞的SIRS分析，用于重建涉及葡萄糖和谷氨酰胺利用的生化途径。这些营养素与能量，合成代谢，免疫调节传感器和与细胞迁移相关的细胞外基质因子有关的生化途径将在具有主要驱动基因异常，正常上皮细胞和相关的stromal细胞的LC细胞中映射。 SA2：养分可用性与缺氧结合使用的探针相互作用。我们将重点关注两个关键问题：1）杜松子酒如何减轻LC细胞的葡萄糖需求？ 2）杜松子酒代谢对低氧LC细胞至关重要吗？ SAS：检查与人类肿瘤相关巨噬细胞中的ARG代谢与杜松子酒的函数。将响应免疫激活剂（B-葡聚糖）和M2对ML极化，将探测与肿瘤相关的人类巨噬细胞中与免疫调节相关性的杜松子酒和ARG利用途径。从该项目中获得的知识将用于解释从项目2和3获得的数据。