Dietary lipids and Experimental IgA Nephropathy

膳食脂质与实验性 IgA 肾病

• 批准号: 7048194
• 负责人: James J Pestka
• 金额: $ 25.37万
• 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 2009-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7048194
• 关键词: IgA nephropathy; Kupffer' s cell; cAMP response element binding protein; chemotherapy; diet therapy; dietary lipid; enzyme activity; gel mobility shift assay; gene environment interaction; gene expression; genetic transcription; immunopathology therapy; inflammation; laboratory mouse; lipid raft; liver cells; macrophage; marine animal oil; nonhuman therapy evaluation; nutrition related tag; phosphoprotein phosphatase; protein kinase; serine; threonine; tissue /cell culture; unsaturated fatty acids

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.

描述(申请人提供)：慢性炎症性疾病在美国每年影响数百万人，并对发病率、死亡率和医疗费用造成很大影响。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(如IgA肾病、类风湿性关节炎、牛皮癣、动脉粥样硬化和狼疮)都是有效的。尽管目前有近2600万美国成年人摄入n-3多不饱和脂肪酸，但这些补充剂的作用机制仍不完全清楚。具体地说，在我们关于n-3多不饱和脂肪酸如何减弱导致炎症性疾病的炎性基因表达的知识中存在着一个关键的缺口。最近对霉菌毒素诱导的小鼠IgA肾病模型的研究表明，n-3PUFAs靶向白介素6(IL-6)的转录调控，而IL-6是导致异常IgA升高的关键因素。本研究的目的是阐明n-3多不饱和脂肪酸抑制转录因子CREB激活和基因转录的具体机制。我们的中心假设是，n-3多不饱和脂肪酸破坏了巨噬细胞中CREB激活和CRE下游介导的基因转录的调节。为了验证这一假设，我们的研究团队将使用通过饮食或培养暴露于n-3多不饱和脂肪酸的巨噬细胞来阐明CREB磷酸化和IL-6和其他基因的下游转录是如何被抑制的。中心假说将通过以下几个方面得到验证：(1)摄入n-3PUFA对巨噬细胞中CREB激酶的影响与CREB激活的关系；(2)摄入n-3PUFA对巨噬细胞中丝氨酸/苏氨酸蛋白磷酸酶CREB激活的影响；(3)表征n-3PUFA对Cre介导的转录的相对于靶基因和组织的特异性。预计这项工作将产生几个结果。首先，我们希望对n-3多不饱和脂肪酸干扰炎症基因转录的分子基础有一个更好的理解。其次，这里开发的模型将直接告知医务人员n-3PUFA补充剂对预防/治疗IgAN和其他涉及炎症基因诱导的疾病的适用性，以及适当的n-3PUFA组织水平和剂量。第三，这项研究将产生重要的新的安全信息，即n-3多不饱和脂肪酸在组织中与天然免疫系统无关的潜在有害影响。总而言之，这些结果将对人类健康产生积极影响，为产生相对于大量美国人消费的一类重要营养补充剂的合理公共卫生建议提供科学基础。