Glycine metabolism in cancer - Research Supplement to Promote Diversity in Health-Related Research; Velasco

癌症中的甘氨酸代谢 - 促进健康相关研究多样性的研究增刊；

• 批准号: 10064354
• 负责人: Gregory S Ducker
• 金额: $ 4.26万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-12-01 至 2021-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10064354
• 关键词: Address; Advanced Malignant Neoplasm; Affect; Amino Acids; Antioxidants; Award; B-Cell Lymphomas; Bioavailable; Biological Assay; Blood Cells; Cancer Cell Growth; Cancer Model; Cancer cell line; Carbon; Catabolic Process; Catabolism; Cell Line; Cell Survival; Cells; Clinic; Consumption; Culture Media; DNA biosynthesis; Data; Development; Diet; Diet Modification; Dose; Environment; Enzymes; Equilibrium; Folic Acid; Folic Acid Antagonists; Food; Genetic; Glioblastoma; Glutathione; Glycine; Glycine Hydroxymethyltransferase; Growth; Health; Hematologic Neoplasms; Hematology; Homeostasis; Human; Isoenzymes; Isotopes; Lead; Liquid substance; Malignant Neoplasms; Mediating; Membrane Transport Proteins; Metabolic; Metabolism; Mitochondria; Modeling; Mus; Normal Cell; Oxidation-Reduction; Oxidative Stress; Parents; Pathologic; Pathway interactions; Patients; Peptides; Pharmacodynamics; Pharmacology; Positioning Attribute; Process; Production; Proteins; Publishing; Purines; Reaction; Research; Role; Serine; Solid; Source; Starvation; Stress; Techniques; Testing; Therapeutic; Tissues; Tracer; Tumor Cell Line; Tumor-Derived; Universities; Utah; amino acid metabolism; anti-cancer; anticancer research; base; cancer cell; cancer stem cell; career; cell growth; cell type; chemotherapy; combat; drug discovery; experimental study; folic acid metabolism; in vivo; inhibitor/antagonist; large cell Diffuse non-Hodgkin' s lymphoma; metabolomics; mouse model; novel; novel therapeutic intervention; small molecule; small molecule inhibitor; synthetic enzyme; tenure track; tumor; tumor growth; tumor initiators; tumor metabolism; tumor progression; uptake

Project Summary – Parent Award R00CA215307 Cancer cells have a distinct metabolism that supports their pathological proliferation. Targeting this metabolism has led to many of the existing chemotherapies in the clinic today such as antifolates. The amino acid glycine is primarily produced by folate metabolism, a pathway that is nearly universally upregulated in cancer. Glycine supports important biosynthetic processes including protein, purine and glutathione synthesis. In addition, glycine catabolic processes have recently been shown to be important in cancer stem cells and glioblastoma. In newly published data, I demonstrated that glycine-supported antioxidant production is crucial for cancer cell growth. This proposal seeks to quantitatively characterize glycine metabolism in cancer and to test the hypothesis that folate-mediated glycine synthesis supports glutathione production and thus redox homeostasis. In these efforts, I will benefit from a new small molecule that I discovered, which potently inhibits both isozymes of the glycine synthetic enzyme SHMT. In Aim 1, I will use isotope tracers to quantitate glycine production and consumption fluxes in normal and cancer cells, and apply these findings in vivo. I will further use these techniques to identify the membrane transporters that facilitate glycine entry into the cell. In Aim 2, I will test whether changing glycine availability in vivo affects tumor progression. I will do this pharmacologically with an optimized in vivo active SHMT inhibitor in models of hematological malignancy and through diet by modulating the amino acid content in food. Collectively, these experiments will lay the groundwork for targeting of glycine metabolism as a new therapeutic approach in cancer. Supported in my new tenure-track position at the University of Utah, this proposal will launch my independent research career.

项目总结-家长奖R00CA215307 癌细胞有一种独特的新陈代谢，支持它们的病理性增殖。瞄准这种新陈代谢 导致了今天临床上许多现有的化疗药物，如抗叶酸。氨基酸甘氨酸 主要由叶酸代谢产生，这是一种在癌症中几乎普遍上调的途径。甘氨酸 支持重要的生物合成过程，包括蛋白质、嘌呤和谷胱甘肽的合成。此外, 甘氨酸分解代谢过程最近被证明在癌症干细胞和胶质母细胞瘤中是重要的。 在最新发表的数据中，我证明了甘氨酸支持的抗氧化剂的产生对癌细胞至关重要 成长。这一建议试图定量描述癌症中的甘氨酸代谢，并测试 假设叶酸介导的甘氨酸合成支持谷胱甘肽的产生，从而支持氧化还原动态平衡。 在这些努力中，我将受益于我发现的一种新的小分子，它有效地抑制了两种同工酶 甘氨酸合成酶SHMT。 在目标1中，我将使用同位素示踪剂来量化正常和 癌细胞，并将这些发现应用于体内。我将进一步使用这些技术来识别膜 促进甘氨酸进入细胞的转运体。在目标2中，我将测试改变甘氨酸在 活体影响肿瘤的进展。我会用一种体内优化的活性SHMT抑制剂进行药理学研究 在血液系统恶性肿瘤模型中，通过饮食调节食物中的氨基酸含量。 总之，这些实验将为甘氨酸代谢作为一种新的靶向奠定基础。 癌症的治疗方法。支持我在犹他大学的新终身教职，这 提案将开启我的独立研究生涯。