Dietary lipids and Experimental IgA Nephropathy

膳食脂质与实验性 IgA 肾病

• 批准号: 7215581
• 负责人: James J Pestka
• 金额: $ 24.61万
• 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/7215581
• 关键词: Address; Adult; Affect; American; Atherosclerosis; Attenuated; Binding; Caring; Cells; Chronic; Class; Clinical Research; Consult; Consumption; Cyclic AMP-Responsive DNA-Binding Protein; Diet; Dietary Fats; Disease; Disruption; Ensure; Event; Fatty Acids; Figs - dietary; Fish Oils; Gene Expression; Gene Targeting; Genes; Genetic Transcription; Grant; Health; Health Care Costs; Hepatocyte; Human; IL6 gene; Immune; Immune system; Immunoglobulin A; Impairment; Inflammation; Inflammatory; Ingestion; Ink; Intake; Interleukin-6; Kidney Diseases; Knowledge; Kupffer Cells; Laboratories; Lupus; Lymphoid Tissue; Mediating; Medical; Membrane Microdomains; Metabolic; Mitogen-Activated Protein Kinases; Modeling; Molecular; Morbidity - disease rate; Mus; Mycotoxins; Numbers; Outcome; Pathway interactions; Phosphoric Monoester Hydrolases; Phosphorylation; Phosphotransferases; Polyunsaturated Fatty Acids; Prevention; Prophylactic treatment; Protein Kinase; Protein Phosphatase 2A Regulatory Subunit PR53; Protein phosphatase; Proteins; Proto-Oncogene Proteins c-akt; Psoriasis; Public Health; Publishing; Qualifying; RPS6KA5 gene; Recommendation; Regulation; Relative (related person); Reporting; Research; Research Design; Research Personnel; Rheumatoid Arthritis; Role; Safety; Signal Transduction; Specificity; Stimulus; Supplementation; Testing; Therapeutic; Tissues; Toxin; Transcriptional Regulation; Transduction Gene; Up-Regulation; Work; base; deoxynivalenol; dietary supplements; dosage; feeding; gene induction; immune function; improved; innovation; macrophage; microbial; mortality; mouse model; programs; protein activation; sound; success; transcription factor

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（由申请人提供）：慢性炎症性疾病每年影响美国数百万人，并对发病率、死亡率和医疗保健费用有广泛影响。临床研究表明，食用鱼油中的n-3多不饱和脂肪酸（PUFA）可有效预防和治疗炎症性疾病，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。尽管目前有近2600万美国成年人食用n-3 PUFA，但这些补充剂的作用机制仍不完全清楚。具体而言，我们对n-3 PUFA如何减弱导致炎性疾病的炎性基因表达的认识存在重大差距。真菌毒素诱导的小鼠IgAN模型的最新研究表明，n-3 PUFAs靶向白细胞介素-6（IL-6）的转录调节，这对于异常的伊加超高至关重要。本提案的目的是阐明n-3 PUFA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 PUFA破坏调节CREB激活和下游CREB介导的基因转录在巨噬细胞。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 PUFA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。将通过以下研究来检验中心假设：（1）将n-3 PUFA摄入对CREB激酶的影响与巨噬细胞中CREB活化相关联;（2）将n-3 PUFA摄入对巨噬细胞中Ser/Thr蛋白磷酸酶CREB活化的影响相关联;（3）表征n-3 PUFA对相对于靶基因和组织的CREB介导的转录的影响的特异性。预计这项工作将产生若干成果。首先，我们希望有一个更好的了解的分子基础，n-3多不饱和脂肪酸干扰炎症基因转录。其次，这里开发的模型将直接告知医疗保健工作者n-3 PUFA补充剂用于预防/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-3 PUFA组织水平和剂量。第三，这项研究将产生关于n-3 PUFA在与先天免疫系统无关的组织中的潜在有害影响的重要新安全性信息。总的来说，这些结果将通过提供科学依据来产生与大量美国人消费的一类重要营养补充剂相关的合理公共卫生建议，从而对人类健康产生积极影响。