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: 8123466
• 负责人: Joseph E Qualls
• 金额: $ 4.65万
• 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 2012-07-27
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8123466
• 关键词: Address; Animal Model; Apoptosis; Arginine; Asthma; B-Lymphocytes; Bladder; Cells; Characteristics; Environment; Enzymes; Equilibrium; Event; Free Radicals; Gene Expression; Genetic; Goals; Growth; Growth and Development function; Health; 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 prostate; 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; T-Lymphocyte; Testing; Tissues; Toxic effect; Treatment Protocols; Vasodilation; Work; Wound Healing; angiogenesis; arginase; cytokine; enzyme activity; macrophage; malignant breast neoplasm; neoplastic cell; outcome forecast; oxidation; 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)：肿瘤相关巨噬细胞(TAM)目前被认为是肿瘤进展的关键。尿素循环酶精氨酸酶1(Arg1)的表达增加与TAMS密切相关。关于Arg1在功能中的S作用的一种假说是，Arg1通过消耗一氧化氮合酶和精氨酸酶的共同底物L-精氨酸来调节一氧化氮(NO)的产生。本研究的总体目标是探讨精氨酸、诱导型一氧化氮合酶、L-精氨酸代谢和自由基产生在肿瘤发生、生长和基因表达修饰中的作用。我们的工作假设是Arg1是一种必需的酶 实体肿瘤进展及其从TAMS中消除将导致肿瘤进展减慢和/或 NO调节、血管生成和免疫逃避中至关重要的代偿机制的发现 肿瘤。我们将使用独特的基因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，其中我们可以通过多种方式操纵MO L-精氨酸代谢，特别是在TAMs中。拟议的实验结果将阐明功能和肿瘤免疫反应的新方面。这些实验将针对以下目标：目的1-确定Arg1通过L-精氨酸的代谢调节TAMS产生NO的机制，目的2-确定TAMS产生基质金属蛋白酶(MMPs)对Arg1的需求，以及目标3-确定实体瘤生存对Arg1的需求。每一个目标都将通过将实体肿瘤植入Arg1/Flox；Tie2cre(其中MOS不能产生Arg1)和对照组小鼠来实现。当TAMs能够或不能产生Arg1时，将从肿瘤中分离TAMs，并分析其基因表达、蛋白质产生和肿瘤进展控制。公共卫生相关性：TAMs通常与癌症预后不良有关，包括乳腺癌、前列腺癌和膀胱癌。Arg1在大多数肿瘤中大量表达，推测其主要由TAMs表达。本研究的主要目的是确定Arg1的表达与功能之间的联系，以及它们与相关肿瘤的相互关系。所获得的信息将导致针对免疫细胞和肿瘤的更好的治疗方案。