Role of TAM Arginase 1 in Tumor Progression

TAM 精氨酸酶 1 在肿瘤进展中的作用

• 批准号: 7615323
• 负责人: Joseph E Qualls
• 金额: $ 5.01万
• 依托单位: ST. JUDE CHILDREN'S RESEARCH HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2012-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7615323
• 关键词: Address; Animal Model; Apoptosis; Arginine; Asthma; B-Lymphocytes; Bladder; Breast; Cells; Characteristics; Environment; Enzymes; Equilibrium; Event; Free Radicals; Gene Expression; Genetic; Goals; Growth; Growth and Development function; Immune; Immune Targeting; Immune response; Immunosuppression; Implant; In Situ; Infection; Inflammation; Interstitial Collagenase; Laboratories; Lead; Link; Lymphocyte; MMP2 gene; MMP9 gene; Malignant Neoplasms; Malignant neoplasm of urinary bladder; Matrix Metalloproteinases; Mediating; Metabolism; Metalloproteinase Gene; Methods; Modeling; Modification; Mus; Mutagenesis; Natural Killer Cells; Neoplasm Metastasis; Nitric Oxide; Nitric Oxide Synthase; Ornithine Decarboxylase; Outcome; Peptide Hydrolases; Production; Prostate; Proteins; Quail; Regulation; Role; Solid; Solid Neoplasm; Staging; Testing; Tissues; Toxic effect; Treatment Protocols; Vasodilation; Work; Wound Healing; angiogenesis; arginase; cytokine; enzyme activity; macrophage; malignant breast neoplasm; neoplastic cell; outcome forecast; oxidation; public health relevance; research study; response; tool; tumor; tumor growth; tumor progression; tumorigenesis; tumorigenic; urea cycle

DESCRIPTION (provided by applicant): Tumor associated macrophages (TAMs) are currently thought to be critical for tumor progression. Increased expression of the urea cycle enzyme arginase 1 (Arg1) is closely correlated with TAMs. One hypothesis for Arg1's role in TAM function is that Arg1 regulates nitric oxide (NO) production by depleting L-arginine, the common substrate of nitric oxide synthases and arginases. The overall goal of this proposal is to investigate the functions of TAM Arg1, iNOS, L-arginine metabolism and free radical production in tumor development, growth and gene expression modification. Our working hypothesis is that Arg1 is an essential enzyme in solid tumor progression and its elimination from TAMs will lead to reduced tumor progression and/or the discovery of compensatory mechanisms vital to NO regulation, angiogenesis, and immune evasion by tumors. We will test the functions of Arg1, NO, and macrophage (MO) L-arginine metabolism in solid tumor models using unique genetic tools where we can manipulate MO L-arginine metabolism, specifically in TAMs, in multiple ways. The outcomes of the proposed experiments will illuminate new aspects of TAM function and immune responses in tumors. The experiments proposed will address the following aims: Aim 1 - Determine the mechanistic aspects of Arg1-mediated regulation of NO production by TAMs through the metabolism of L-arginine, Aim 2 - Determine the requirement for Arg1 in the production of matrix metalloproteinases (MMPs) by TAMs, and Aim 3 - Determine the requirement for TAM Arg1 for solid tumor survival. Each of the aims will be achieved by implanting solid tumors into Arg1flox/flox;Tie2cre (in which MOs cannot produce Arg1) and control mice. TAMs will be isolated from the tumor and analyzed for gene expression, protein production, and control of tumor progression when they can, or cannot, produce Arg1. PUBLIC HEALTH RELEVANCE: TAMs are generally associated with poor prognosis in cancer, including breast, prostate, and bladder cancers. Arg1 is expressed in large amounts in most tumors, and its expression is assumed to be primarily by TAMs. The major goal of this proposal is to determine the link between Arg1 expression and TAM function, and their interrelationship with associated tumors. The information gained will lead to better treatment regimens targeting immune cells, as well as the tumor.

描述（由申请人提供）：目前认为肿瘤相关的巨噬细胞（TAM）对于肿瘤进展至关重要。 尿素周期精氨酸酶1（ARG1）的表达增加与TAM密切相关。 ARG1在TAM功能中的作用的一种假设是，ARG1通过消耗L-精氨酸（一氧化氮合酶和精氨酸酶的常见底物）来调节一氧化氮（NO）的产生。 该提案的总体目标是研究TAM ARG1，INOS，L-精氨酸代谢和自由基生产在肿瘤发育，生长和基因表达修饰中的功能。 我们的工作假设是Arg1是一种重要的酶 实体瘤进展及其从TAM中消除将导致肿瘤进展减少和/或 发现没有调节，血管生成和免疫逃避至关重要的补偿机制 肿瘤。 我们将使用独特的遗传工具在实体瘤模型中测试Arg1，NO和巨噬细胞（MO）L-精氨酸代谢的功能，在这些工具中我们可以通过多种方式操纵Mo L-精氨酸代谢，特别是在TAM中。 提出的实验的结果将阐明TAM功能的新方面和肿瘤中的免疫反应。 提出的实验将解决以下目的：目标1-确定ARG1介导的NO生产调节TAM通过L-精氨酸代谢对NO生产的机理方面，目标2-确定ARG1在生产矩阵金属蛋白酶（MMPS）中的ARG1需求，AIM 3-确定对TAM ARG1的固体需求。 每个目标都可以通过将实体瘤植入arg1flox/flox; tie2cre（其中MOS无法产生ARG1）和对照小鼠来实现。 TAM将从肿瘤中分离出来，并分析基因表达，蛋白质产生以及肿瘤进展的控制，或者在可能产生ARG1时。 公共卫生相关性：TAM通常与癌症的预后不良有关，包括乳房，前列腺和膀胱癌。 Arg1在大多数肿瘤中大量表达，其表达主要由TAMS表示。 该提案的主要目的是确定ARG1表达与TAM功能之间的联系，以及它们与相关肿瘤的相互关系。 获得的信息将导致靶向免疫细胞以及肿瘤的更好的治疗方案。