Dietary lipids and Experimental IgA Nephropathy

描述（由申请人提供）：慢性炎症性疾病每年影响数百万美国人，并广泛导致发病率，死亡率和医疗保健成本。临床研究表明，食用鱼油中的n-3多不饱和脂肪酸（PUFAs）对预防和治疗炎症性疾病有效，如IgA肾病（IgAN）、类风湿性关节炎、牛皮癣、动脉粥样硬化和狼疮。尽管目前有近2600万美国成年人摄入n-3 PUFAs，但这些补充剂的作用机制仍不完全清楚。具体来说，我们对n-3 PUFAs如何减弱导致炎症性疾病的炎症基因表达的认识存在一个关键的空白。最近对真菌毒素诱导的IgAN小鼠模型的研究表明，n-3 PUFAs靶向白介素-6 （IL-6）的转录调节，IL-6是异常IgA高升高的关键。本提案的目的是阐明n-3 PUFAs抑制转录因子CREB激活和由此产生的基因转录的具体机制。我们的中心假设是n-3 PUFAs破坏巨噬细胞中CREB激活和下游CREB介导的基因转录的调节。为了验证这一假设，我们的研究小组将使用通过饮食或培养暴露于n-3 PUFAs的巨噬细胞来阐明CREB磷酸化和IL-6和其他基因的下游转录是如何被抑制的。中心假设将通过以下研究来验证：(1)巨噬细胞中n-3 PUFA摄入对CREB激酶的影响与CREB激活的关系；(2) n-3 PUFA摄入对巨噬细胞丝氨酸/苏氨酸蛋白磷酸酶CREB激活的影响；(3)表征n-3 PUFA相对于靶基因和组织对cre介导转录的特异性。预计这项工作将产生若干结果。首先，我们期望对n-3 PUFAs干扰炎症基因转录的分子基础有更好的理解。其次，本文建立的模型将直接告知医护人员补充n-3 PUFA在预防/治疗IgAN和其他涉及炎症基因诱导的疾病以及适当的n-3 PUFA组织水平和剂量方面的适用性。第三，本研究将提供关于n-3 PUFAs在与先天免疫系统无关的组织中潜在有害影响的重要新安全性信息。总的来说，这些结果将通过为产生健全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，这些建议与大量美国人食用的一类重要营养补充剂有关。

DESCRIPTION (provided by applicant): 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, our research 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.