MINORITY PREDOCTORAL FELLOWSHIP PROGRAM

少数族裔博士前奖学金计划

• 批准号: 6919950
• 负责人: COURTNEY G WOODS
• 金额: $ 3.42万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-01 至 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6919950
• 关键词: Kupffer' s cell; NAD(P)H dehydrogenase; RNase protection assay; apoptosis; cell proliferation; chemical carcinogen; chemical carcinogenesis; electron spin resonance spectroscopy; enzyme activity; free radicals; gene expression profiling; genetic transcription; genetically modified animals; laboratory mouse; messenger RNA; microarray technology; molecular oncology; oxidizing agents; peroxisome proliferator activated receptor; predoctoral investigator; protein protein interaction; tissue /cell culture; tumor necrosis factor alpha

DESCRIPTION (provided by applicant): Peroxisome proliferators (PPs) are a class of agents that are ubiquitous in the environment and are categorized as high-volume production chemicals. Many of these agents are very potent rodent liver carcinogens but it is not clear whether they are carcinogenic to humans. The mechanism of action of PPs is non-genotoxic and involves increases in peroxisomal activity and cell proliferation in liver. While PPs have been studied extensively, uncertainty remains regarding the exact mechanism and the basis for species differences. Two key players in the mode of action of these agents are nuclear receptor PPAR-alpha in parenchymal cells, known to be required for liver cancer in rodents, and TNF-alpha, a mitogenic cytokine in Kupffer cells that induces cell proliferation. The goal of this research is to develop a better understanding of the molecular pathways by which PPAR-alpha and TNF-alpha are involved in rodent tumorigenesis. We hypothesize that PPs cause increased oxidant production in Kupffer cells, which signal activation of TNF-alpha and other mitogenic cytokines that require PPAR-alpha for rapid hepatic cell proliferation. The findings of this research will help in assessing human risk to these and perhaps other non-genotoxic carcinogens.

描述（由申请人提供）：过氧化物酶体增殖剂（PP）是一类在环境中普遍存在的物质，被归类为大批量生产化学品。其中许多物质是非常有效的啮齿动物肝脏致癌物，但尚不清楚它们是否对人类具有致癌性。 PP 的作用机制是非遗传毒性的，涉及增加肝脏过氧化物酶体活性和细胞增殖。虽然 PP 已被广泛研究，但其确切机制和物种差异的基础仍然存在不确定性。这些药物作用方式中的两个关键角色是实质细胞中的核受体 PPAR-α（已知是啮齿动物肝癌所需的）和 TNF-α（库普弗细胞中诱导细胞增殖的促有丝分裂细胞因子）。本研究的目的是更好地了解 PPAR-α 和 TNF-α 参与啮齿动物肿瘤发生的分子途径。我们假设 PP 会导致 Kupffer 细胞中氧化剂的产生增加，从而发出 TNF-α 和其他促有丝分裂细胞因子激活的信号，而这些细胞因子需要 PPAR-α 来实现肝细胞的快速增殖。这项研究的结果将有助于评估人类对这些以及其他非基因毒性致癌物的风险。