Dietary lipids and Experimental IgA Nephropathy

慢性炎症性疾病每年影响美国数百万人，并对 发病率、死亡率和医疗费用。临床研究表明，n-3多不饱和脂肪酸的摄入量 鱼油中的脂肪酸(PUFAs)对预防和治疗炎症性疾病都很有效 如IgA肾病(IgAN)、类风湿关节炎、牛皮癣、动脉粥样硬化和狼疮。虽然差一点 目前有2600万美国成年人消费n-3多不饱和脂肪酸，这些补充剂的作用机制仍然存在 不完全理解。具体地说，我们对n-3个多不饱和脂肪酸如何衰减的了解存在一个关键差距。 导致炎症性疾病的炎性基因的表达。霉菌毒素的最新研究- 诱导的小鼠IgAN模型提示n-3PUFAs靶向IL-6转录调控 这对反常的免疫球蛋白A升高至关重要。这项提议的目的是澄清具体的 N-3多不饱和脂肪酸抑制转录因子CREB及其合成基因激活的机制 抄写。我们的中心假设是n-3多不饱和脂肪酸破坏了CREB激活的调节，并 Cre下游介导的巨噬细胞基因转录。为了验证这一假设，我们的研究 研究小组将通过饮食或培养方式使用暴露于n-3多不饱和脂肪酸的巨噬细胞来阐明CREB是如何 IL-6和其他基因的磷酸化和下游转录受到抑制。中环 将通过追求以下假设来检验假设：(1)n-3多不饱和脂肪酸摄入对CREB激酶的相关影响 巨噬细胞CREB活化；(2)n-3多不饱和脂肪酸摄入对Ser/Thr蛋白磷酸酶的相关影响 巨噬细胞中CREB的激活；(3)n-3多不饱和脂肪酸对CRE介导作用的特异性 相对于目标基因和组织的转录。预计这项工作将产生几个结果。 首先，我们期望对n-3多不饱和脂肪酸干扰的分子基础有一个更好的理解。 与炎症基因转录有关。其次，这里开发的模型将直接为医疗保健提供信息 N-3多不饱和脂肪酸补充剂对预防/治疗IgA肾病及其他疾病的适用性 涉及炎症基因诱导的疾病以及适当的n-3多不饱和脂肪酸组织水平和 剂量。第三，这项研究将产生关于潜在有害物质的重要新的安全信息 N-3多不饱和脂肪酸在组织中的作用与天然免疫系统无关。总体而言，这些结果将 为制定合理的公共卫生建议提供科学依据，从而对人类健康产生积极影响 与大量美国人消费的一种重要的营养补充剂相关的饮食。

Chronic inflammatory diseases impact millions of people in the U.S. annually and contribute extensively to morbidity, mortality and health care costs. Clinical studies suggest that consumption of n-3 polyunsaturated fatty acids (PUFAs) from fish oil is efficacious for both prevention and treatment of inflammatory diseases such as IgA nephropathy (IgAN), rheumatoid arthritis, psoriasis, atherosclerosis and lupus. Although nearly 26 million U.S. adults currently consume n-3 PUFAs, mechanisms of action of these supplements remain incompletely understood. Specifically, a critical gap exists in our knowledge of how n-3 PUFAs attenuate expression of inflammatory genes that contribute to inflammatory diseases. Recent studies of mycotoxin- induced mouse model of IgAN suggest that n-3 PUFAs target transcriptional regulation of interleukin-6 (IL-6) which is critical for aberrant IgA hyperelevation. The objective of this proposal is to elucidate the specific mechanisms by which n-3 PUFAs suppress activation of the transcription factor CREB and resultant gene transcription. Our central hypothesis is that n-3 PUFAs disrupt regulation of CREB activation and downstream CRE-mediated gene transcription in the macrophage. To test this hypothesis, ourresearch team will use macrophages exposed to n-3 PUFAs via diet or in culture to elucidate how CREB phosphorylation and downstream transcription of IL-6 and other genes are suppressed. The central hypothesis will be tested by pursuing the following (1) Relate effects of n-3 PUFA intake on CREB kinases to CREB activation in the macrophage; (2) Relate effects of n-3 PUFA intake on Ser/Thr protein phosphatases CREB activation in the macrophage; (3) Characterize specificity of n-3 PUFA effects on CRE-mediated transcription relative to target genes and tissue. Several outcomes are anticipated to arise from this work. First, we expect to have an improved understanding of the molecular basis by which n-3 PUFAs interfere with inflammatory gene transcription. Second, the models developed here will directly inform medical care workers on the applicability of n-3 PUFA supplementation for prophylaxis/treatment of IgAN and other diseases that involve inflammatory gene induction as well as appropriate n-3 PUFA tissue levels and dosages. Third, this research will yield important new safety information regarding potential deleterious affects of n-3 PUFAs in tissue not related to the innate immune system. Collectively, these outcomes will positively impact human health by providing a scientific basis for generating sound public health recommen- dations relative to an important class of nutritional supplements consumed by a large number of Americans.