DIETARY LIPIDS AND EXPERIMENTAL IGA NEPHROPATHY

膳食脂质和实验性 IGA 肾病

• 批准号: 6489757
• 负责人: James J Pestka
• 金额: $ 21.76万
• 依托单位: MICHIGAN STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-02-01 至 2004-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6489757
• 关键词: IgA nephropathy; JUN kinase; chemoprevention; diet therapy; dietary lipid; disease /disorder model; enzyme activity; genetic transcription; immunoglobulin A; immunopathology therapy; interleukin 6; laboratory mouse; macrophage; marine animal oil; mitogen activated protein kinase; mycotoxins; nonhuman therapy evaluation; northern blottings; nutrition related tag; omega 3 fatty acid; polymerase chain reaction; tissue /cell culture; tocopherols; transcription factor; western blottings

DESCRIPTION: The goal of this research will be to understand specific mechanisms by which dietary polyunsaturated fatty acids (n-3 PUFA) in marine and plant oils impair development and progression of immunoglobulin A nephropathy (IgAN). Although IgAN is the most common glomerulonephritis worldwide, effective treatments for it remain elusive. Fish oil consumption has recently shown promise in retarding disease progression and renal failure in IgAN patients. An experimental mouse model is now available in which immunopathological hallmarks of IgAN are induced by dietary exposure to the mycotoxin vomitoxin (VT). Interestingly, replacement of corn oil in a semi-purified diet with menhaden fish oil markedly impairs immunopathogenesis in this model. The sequential activation of mitogen-activated protein kinases (MAPKs), up-regulation of interleukin-6 (IL-6) gene expression and polyclonal activation of IgA-secreting cells appear to be critical early events in VT-induced IgAN. The guiding hypothesis for this project is that ingestion of n-3 PUFA in fish oil attenuates VT-induced IgAN by interfering with upstream regulation of IL-6 gene expression. Five specific aims are proposed. In AIM 1, a sub-chronic VT feeding model will be used to determine the capacity of feeding fish oil or the n-3 PUFAs, eicosapentaenoic acid (EPA) or docosahexaenoic acid (DHA), to attenuate VT-induced IgAN markers. In AIM 2, an acute VT exposure model will be used to evaluate the in vivo and ex vivo effects of feeding fish oil on IL-6 and IgA expression. In AIM 3, the role of transcription in n-3 PUFA-attenuated IL-6 expression will be assessed in VT-treated macrophage cultures by measuring transcription factor binding and nuclear runoff of IL-6 mRNA. In AIM 4, the role of post-transcriptional mechanisms in n-3 PUFA-attenuated IL-6 expression will be evaluated by measuring IL-6 mRNA stability in macrophage cultures. In AIM 5, the effects of n-3 PUFAs on activation of the MAPKs SAPK/JNK 1/2, ERK1/2 and p38 will be assessed in macrophages cultured with VT. Long-term impacts of increased mechanistic understanding of n-PUFA effects in this model may include improved nutritional and pharmacological strategies for inhibiting the progression of IgAN and potentially other autoimmune diseases.

描述：本研究的目标是了解特定的 膳食中多不饱和脂肪酸（n-3 PUFA）在海洋中的作用机制 和植物油损害免疫球蛋白A的发育和进展 肾病（IgAN）。虽然IgAN是最常见的肾小球肾炎， 在世界范围内，对它的有效治疗仍然难以捉摸。鱼油的消费量 最近显示出在延缓疾病进展和肾衰竭方面的前景， IgAN患者。现在有一种实验小鼠模型， IgAN的免疫病理学特征是由饮食暴露于 霉菌毒素呕吐毒素（VT）。有趣的是，玉米油的替代品 含鲱鱼鱼油的半纯化饮食显著削弱免疫发病机制 in this model模型.丝裂原活化蛋白激酶的顺序激活 （MAPKs）、白细胞介素-6（IL-6）基因表达上调和多克隆 IgA分泌细胞的激活似乎是关键的早期事件， VT诱导的IgAN。该项目的指导假设是， 鱼油中的n-3 PUFA通过干扰上游免疫抑制因子而减弱VT诱导的IgAN IL-6基因表达的调控。提出了五个具体目标。在AIM 1中， 将使用亚慢性VT喂养模型来确定 喂食鱼油或n-3 PUFA、二十碳五烯酸（EPA）或 二十二碳六烯酸（DHA），以减弱VT诱导的IgAN标志物。在AIM 2中， 急性室性心动过速暴露模型将用于评价体内和离体 鱼油对IL-6和伊加表达的影响。在AIM 3中， 将评估n-3 PUFA减弱的IL-6表达中的转录， VT处理的巨噬细胞培养物，通过测量转录因子结合和 IL-6 mRNA的核径流。在AIM 4中，转录后的作用 将通过以下方法评价n-3 PUFA减弱的IL-6表达的机制： 测量巨噬细胞培养物中IL-6 mRNA的稳定性。在AIM 5中， n-3 PUFA对MAPK SAPK/JNK 1/2、ERK 1/2和p38的激活作用将是 在用VT培养的巨噬细胞中评估。增加的长期影响 在该模型中，对n-PUFA效应的机制理解可能包括改善 营养和药理学策略，以抑制进展， IgAN和潜在的其他自身免疫性疾病。