DIETARY LIPIDS AND EXPERIMENTAL IGA NEPHROPATHY

描述：这项研究的目标将是了解具体的 海洋中膳食多不饱和脂肪酸(n-3 PUFA)的作用机制 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。鱼油消费已经 最近显示出在延缓疾病进展和肾功能衰竭方面的前景 伊根病患。一种实验性的小鼠模型现已问世 IgAN的免疫病理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 半纯鱼油饲料对免疫致病作用的影响 在这个模型中。丝裂原活化蛋白激酶的顺序激活 MAPKs、IL-6基因表达上调与多克隆 IgA分泌细胞的激活似乎是急性胰腺炎的关键早期事件 VT诱导的IgAN。这个项目的指导性假设是摄取 鱼油中N-3多不饱和脂肪酸通过干扰上游抑制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， 将使用亚慢性VT喂养模型来确定 饲喂鱼油或n-3多不饱和脂肪酸、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，一个 急性VT暴露模型将用于评估体内和体外 饲喂鱼油对IL-6和IgA表达的影响在AIM 3中， 在n-3PUFA减弱的IL-6表达中的转录将在 VT处理巨噬细胞后通过检测转录因子结合和 核内流出IL-6mRNA。在AIM 4中，转录后蛋白的作用 N-3PUFA抑制IL-6表达的机制将通过以下方式进行评估 测定巨噬细胞培养中IL-6mRNA的稳定性。在AIM 5中， 激活MAPK SAPK/JNK 1/2、ERK1/2和p38的N-3个多不饱和脂肪酸 在VT培养的巨噬细胞中进行评估。增加的长期影响 对该模型中n-多不饱和脂肪酸影响的机理理解可能包括改进 抑制糖尿病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。

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.