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：这项研究的目标是了解具体的 膳食多不饱和脂肪酸（n-3 PUFA）在海洋中的作用机制 和植物油会损害免疫球蛋白 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，有效的治疗方法仍然难以捉摸。鱼油消费量有 最近显示出在延缓疾病进展和肾功能衰竭方面的前景 IgAN 患者。现已推出实验性小鼠模型，其中 IgAN 的免疫病理学特征是由饮食中暴露于 霉菌毒素呕吐毒素（VT）。有趣的是，用玉米油替代 含有鲱鱼油的半纯化饮食显着损害免疫发病机制 在这个模型中。丝裂原激活蛋白激酶的顺序激活 (MAPK)、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。该项目的指导性假设是摄入 鱼油中的 n-3 PUFA 通过干扰上游来减弱 VT 诱导的 IgAN IL-6 基因表达的调控。提出了五个具体目标。在目标 1 中， 亚慢性 VT 喂养模型将用于确定 喂养鱼油或 n-3 PUFA、二十碳五烯酸 (EPA) 或 二十二碳六烯酸 (DHA)，可减弱 VT 诱导的 IgAN 标记物。在 AIM 2 中， 急性VT暴露模型将用于评估体内和离体 饲喂鱼油对 IL-6 和 IgA 表达的影响。在 AIM 3 中，角色 n-3 PUFA 减弱的 IL-6 表达中的转录将在 通过测量转录因子结合和 VT 处理的巨噬细胞培养物 IL-6 mRNA 的核径流。在 AIM 4 中，转录后的作用 n-3 PUFA 减弱 IL-6 表达的机制将通过以下方式进行评估 测量巨噬细胞培养物中 IL-6 mRNA 的稳定性。在 AIM 5 中，效果 激活 MAPK SAPK/JNK 1/2、ERK1/2 和 p38 时的 n-3 PUFA 将被 在 VT 培养的巨噬细胞中进行评估。增加的长期影响 该模型中对 n-PUFA 效应的机制理解可能包括改进 抑制病情进展的营养和药理学策略 IgAN 和其他潜在的自身免疫性疾病。