Dietary lipids and Experimental IgA Nephropathy

慢性炎症性疾病每年影响美国数百万人，并广泛导致 发病率、死亡率和保健费用。临床研究表明，摄入n-3多不饱和脂肪酸 鱼油中的多不饱和脂肪酸（PUFAs）对预防和治疗炎症性疾病都有效 如伊加肾病（IgAN）、类风湿性关节炎、牛皮癣、动脉粥样硬化和狼疮。尽管近 2600万美国成年人目前消费n-3 PUFA，这些补充剂的作用机制仍然存在 不完全理解。具体来说，在我们对n-3 PUFA如何衰减的知识中存在着一个关键的差距。 导致炎性疾病的炎性基因的表达。霉菌毒素的最新研究- IgAN诱导小鼠模型表明n-3 PUFAs靶向白细胞介素-6（IL-6）的转录调节 这对异常的伊加高分泌至关重要。本建议的目的是阐明具体的 n-3 PUFA抑制转录因子CREB和合成基因的激活的机制 转录。我们的中心假设是n-3 PUFA破坏CREB激活的调节， 下游CRE介导的基因转录在巨噬细胞中。为了验证这一假设，我们的研究 研究小组将使用通过饮食或培养暴露于n-3 PUFA的巨噬细胞来阐明CREB如何 IL-6和其它基因的磷酸化和下游转录受到抑制。中央 假设将通过以下方式进行检验：（1）将n-3 PUFA摄入对CREB激酶的影响与 （2）n-3 PUFA摄入对巨噬细胞中丝氨酸/苏氨酸蛋白磷酸酶活性的影响 （3）表征n-3 PUFA对CREB介导的巨噬细胞中CREB活化的作用的特异性。 相对于靶基因和组织的转录。预计这项工作将产生若干成果。 首先，我们期望对n-3 PUFA干扰的分子基础有更好的理解。 与炎症基因转录有关。其次，这里开发的模型将直接告知医疗保健 工作人员对n-3多不饱和脂肪酸补充剂用于预防/治疗IgAN和其他 涉及炎性基因诱导以及适当的n-3 PUFA组织水平的疾病， 剂量.第三，这项研究将产生有关潜在有害物质的重要新安全信息 n-3 PUFA对与先天免疫系统无关的组织的影响。总的来说，这些成果将 通过提供科学依据，为制定合理的公共卫生建议，对人类健康产生积极影响， 相对于大量美国人消费的一类重要的营养补充剂，

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.