MINORITY PREDOCTORAL FELLOWSHIP PROGRAM

少数族裔博士前奖学金计划

• 批准号: 6829944
• 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/6829944
• 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）：过氧化物酶体增殖物（PPS）是在环境中无处不在的一类药物，被归类为大量生产化学品。这些药物中的许多是非常有效的啮齿动物肝癌，但尚不清楚它们是否对人类具有致癌性。 PPS的作用机理是非生物毒性的，涉及肝脏中过氧化物酶体活性和细胞增殖的增加。尽管对PP进行了广泛的研究，但有关物种差异的确切机制和基础的不确定性仍然存在。这些药物的作用方式的两个关键参与者是实质细胞中的核受体PPAR-α，啮齿动物中已知是肝癌所需的，而TNF-alpha是kupffer细胞中促丝分裂细胞因子的TNF-alpha，可引起细胞增殖。这项研究的目的是更好地了解PPAR-Alpha和TNF-Alpha参与啮齿动物肿瘤发生的分子途径。我们假设PP会导致库普弗细胞中的氧化剂产生增加，这表明TNF-α和其他需要PPAR-α进行快速肝细胞增殖的TNF-Alpha和其他有丝分裂细胞因子的激活。这项研究的发现将有助于评估这些甚至其他非生物毒性致癌物的人类风险。