Lung Tumor Promotion by BHT

BHT 促进肺部肿瘤

基本信息

批准号：
7213260
负责人：
ALVIN M MALKINSON
金额：
$ 43.06万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
1982
资助国家：
美国
起止时间：
1982-09-01 至 2009-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7213260
关键词：
3-Methylcholanthrene Adenocarcinoma Adoptive Transfer Affect Alleles Alveolar Anti-Inflammatory Agents Anti-inflammatory Apoptotic Benign Biochemical Bone Marrow Butylated Hydroxytoluene CD44 gene Candidate Disease Gene Carcinogens Cells Characteristics Chemoprevention Chromosomes, Human, Pair 15 Chronic Clinical Chemoprevention Codon Nucleotides Computer Simulation Connexin 43 Development Dinoprostone Distal Dose Enzymes Epithelial Epithelial Cells Epithelium Epoprostenol Event Funding Gene Expression Genes Genetic Genetic Markers Genetic Polymorphism Human Hyperplasia Inbred Strain Inbred Strains Mice Inflammation Inflammatory Inherited Injury Lead Learning Lesion Lipopolysaccharides Lung Lung Neoplasms Malignant neoplasm of lung Maps Mediating Mediator of activation protein Metabolism Modeling Molecular Mus Mutate Mutation Oncogenes Oncogenic Peripheral Pharmaceutical Preparations Phenotype Phosphorylation Play Pneumonectomy Pneumonia Predisposition Preventive Production Prostaglandin Production Prostaglandin-Endoperoxide Synthase Prostaglandins Proto-Oncogenes Quantitative Trait Loci Recombinant Inbred Strain Recombinants Resistance Risk Role Signal Transduction Staging Stimulus Susceptibility Gene Testing Therapeutic Transgenic Mice Translating Tumor Promotion Tumor Suppressor Genes Variant cell type cytokine genetic linkage analysis genome sequencing histogenesis insight intercellular communication lung tumorigenesis macrophage mouse model mutant novel diagnostics response segregation size tumor tumor growth tumor progression tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): Successful chemoprevention of lung cancer requires delineation of those events regulating tumor formation. Mice develop lung tumors with molecular characteristics and histogenesis similar to human pulmonary adenocarcinoma, thus providing a useful model. The only reversible stage in lung tumor progression is promotion, where benign lesions can be induced to revert to silent, non-dividing, mutated cells. We study mechanisms underlying lung tumor promotion by separating induction of the Kras protooncogene mutation that initiates tumorigenesis from application of an agent that promotes tumor development but cannot initiate it, namely, butylated hydroxytoluene (BHT). Reactive metabolites of BHT cause compensatory hyperplasia and inflammation in lungs; we have provided evidence that inflammation plays a major role in promotion. In the next funding period, we will determine how inflammation encourages lung tumor growth. Three Aims are proposed. In Aim I, we will identify genes regulating susceptibility to both the promotion and inflammation induced by BHT using refined linkage analysis with two sets of recombinant inbred (RI) mouse strains that are sensitive and resistant to these actions of BHT, the CXB and AXB, BXA RI strains. Adoptive transfer of bone marrow between sensitive and resistant strains will determine whether these susceptibility genes act through macrophages. In Aim II, possible effects of BHT on allele-specific expression of Kras will be determined; we will learn if BHT enhances tumor growth in mice with an inherited Kras mutation. Also we will modulate the proliferative and inflammatory status in lungs using partial pneumonectomy as a proliferative stimulus along with application of pro-inflammatory drugs or by the use of transgenic mice that over-express pro-inflammatory mediators. In Aim llI, we examine the cell signaling distal to Kras that involves ERK phosphorylation and prostaglandin production in bronchiolar Clara and alveolar type 2 cells isolated from promotion sensitive and resistant mice. We will also examine Cx43 and CD44 as downstream markers of prostaglandin actions on cells. These studies should lead to insights for developing novel diagnostic, preventive, and therapeutic strategies.

描述（由申请人提供）：成功的化学预防肺癌需要描述调节肿瘤形成的事件。小鼠发展具有分子特征和组织发生的肺肿瘤，类似于人类肺腺癌，因此提供了有用的模型。肺部肿瘤进展中唯一可逆的阶段是促进，可以诱导良性病变恢复为静音，非分裂，突变的细胞。我们通过分离诱导KRAS原生物突变的诱导来研究肺部肿瘤促进的机制，从而从促进肿瘤发育但无法引发肿瘤的药物的应用中引发肿瘤发生，即丁基化的羟基甲苯（BHT）。 BHT的反应性代谢物引起肺部补偿性增生和炎症；我们提供了证据表明炎症在促进中起着重要作用。在下一个资金期间，我们将确定炎症如何鼓励肺部肿瘤生长。提出了三个目标。在目标I中，我们将使用精制的连锁分析来确定基因对BHT诱导的促进性和炎症的敏感性，并使用两组重组INBRED（RI）小鼠菌株对BHT，CXB和AXB，BXA RI菌株具有敏感且具有抗性的重组易变（RI）小鼠菌株。敏感和抗性菌株之间骨髓的产物转移将决定这些敏感性基因是否通过巨噬细胞起作用。在AIM II中，将确定BHT对Kras等位基因特异性表达的可能影响；我们将了解BHT是否可以通过遗传的KRAS突变增强小鼠的肿瘤生长。同样，我们还将使用部分肺切除术作为一种增殖刺激来调节肺中的增殖和炎症状态，并使用促炎药或使用过表达促炎性介体的转基因小鼠。在AIM LLI中，我们研究了涉及ERK磷酸化和前列腺素的远端细胞信号传导，该细胞磷酸化和前列腺素的产生和从促进敏感和抗性小鼠中分离出的2型牙槽2型细胞。我们还将检查CX43和CD44作为前列腺素作用对细胞的下游标记。这些研究应导致开发新型诊断，预防和治疗策略的见解。