Dietary Lipids and Silica-Accelerated Autoimmunity

膳食脂质和二氧化硅加速自身免疫

• 批准号: 8260055
• 负责人: James J Pestka
• 金额: $ 23.03万
• 依托单位: MICHIGAN STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-05-11 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8260055
• 关键词: Acceleration; Adult; Affect; American; Antibody Formation; Apoptosis; Area; Asbestos; Autoantigens; Autoimmune Diseases; Autoimmune Process; Autoimmunity; Centers for Disease Control and Prevention (U.S.); Chemoprevention; Chemosensitization; Chronic; Clinical Research; Consumption; Development; Diet; Dietary Factors; Dietary Fats; Disease; Disease Progression; Docosahexaenoic Acids; Effectiveness; Environmental Exposure; Environmental Risk Factor; Epidemiology; Exposure to; Fibrosis; Fish Oils; Food; Foundations; Funding Opportunities; Gene Expression; Genetic Transcription; Glomerulonephritis; Goals; Health; Heavy Metals; Human; Immune system; Immunity; Immunoglobulin A; Indium; Individual; Industry; Inflammation; Inflammatory; Inhalation Exposure; Kidney; Kidney Diseases; Kidney Failure; Knowledge; Language; Lead; Leukocytes; Life Style; Link; Lung; Lung diseases; Lupus; Lupus Nephritis; Mining; Mission; Modeling; Mus; National Institute of Allergy and Infectious Disease; National Institute of Environmental Health Sciences; Nephritis; Nutritional; Occupational Exposure; Occupations; Onset of illness; Outcome; Persons; Pesticides; Plasma Cells; Polyunsaturated Fatty Acids; Prevalence; Prevention; Production; Public Health; Recruitment Activity; Recurrence; Regimen; Renal function; Research; Resolution; Risk; Severities; Silicon Dioxide; Supplementation; Surveys; Systemic Lupus Erythematosus; Testing; Tissues; Toxicant exposure; Trichloroethylene; Trichothecenes; United States National Institutes of Health; Work; abstracting; base; cytokine; improved; insight; lupus prone mice; macrophage; mouse model; preclinical study; prevent; research study; toxicant

DESCRIPTION (provided by applicant): Autoimmune diseases, a constellation of chronic, disabling illnesses that result from the immune system attacking the body's own tissues, are estimated to adversely affect up to 25 million persons in the U.S. The prevalence of autoimmune diseases is markedly impacted by environmental factors (e.g. toxicant exposures) and lifestyle choices (e.g. diet). Notably, the risk of developing systemic lupus erythematosus (lupus), a prototypical autoimmune disease affecting 300,000 Americans and often associated with glomerulonephritis and kidney failure, is increased by occupational exposure (e.g. mining, construction, custodial and manufacturing industries) to silica. Research studies reveal that consumption of n-3 polyunsaturated fatty acids (PUFAs) found in fish oil holds promise for preventing and ameliorating chronic inflammatory diseases including autoimmune nephritis. The specific objective here is to test the hypothesis that consumption of n-3 PUFAs will suppress silica-accelerated nephritis in lupus-prone mice and that this will correspond with decreased leukocyte recruitment and inflammation-associated gene expression in the kidney. This research will be accomplished in two aims. In Aim 1, n-3 PUFA consumption and how it affects latency and severity of silica-accelerated lupus nephritis will be established. In Aim 2, a determination of how n-3 PUFA modulates progression of existing silica-accelerated lupus nephritis will be tested. Consistent with the NIEHS mission, the expected outcomes of these aims will be an increased understanding of how n-3 PUFAs impact silica triggering and exacerbation of autoimmune nephritis. These findings will have a positive impact, because it will be an initial step in the path to predicting how n-3 PUFA consumption might prevent or ameliorate acceleration of autoimmunity by silica and other toxicants. The contribution of this research is expected to be an improved understanding of how n-3 PUFA consumption counteracts the triggering and exacerbation of lupus nephritis by silica. This contribution is significant because it will be the first step in a research continuum that will lead to nutritional strategies to mitigate environmental triggering and exacerbation of autoimmunity. Availability of such preventative and ameliorative strategies would enable individuals who are occupationally exposed to silica to 1) reduce their risk for developing lupus and other autoimmune disease and 2) delay progression of existing autoimmunity by increasing n-3 PUFA consumption via diet and/or supplementation. Furthermore, n-3 PUFA chemoprevention and chemointervention might similarly be applied to workers who are at increased risk of autoimmunity from exposures to toxicants such as asbestos, heavy metals, trichloroethylene, and pesticides. Finally, it is expected that these studies will reveal additional potential benefits of n-3 PUFA consumption on silica-induced lung disease and fibrosis, another understudied area. PUBLIC HEALTH RELEVANCE: For NIH and other PHS agencies applications, this attachment will reflect the second component of the Project Summary. The second component of the Project Summary/Abstract (i.e., "Description") is Relevance. Using no more than two or three sentences, describe the relevance of this research to public health. In this section, be succinct and use plain language that can be understood by a general, lay audience. Systemic Lupus Erythematosus (lupus), an autoimmune disease resulting from the body's production of antibodies against self and production of destructive molecules, has been estimated to affect 300K Americans with approximately half of these individuals developing nephritis, a debilitating condition that can lead to loss of kidney function. Exposure to silica, the earth's most abundant element, in common occupations such as construction, mining, faming and manufacturing increases an individual's risk of developing lupus. Based on recent evidence linking consumption of docosahexaenoic acid (DHA), a food component commonly found in fish oil, to prevention and amelioration of autoimmune nephritis, we propose to investigate the potential for a DHA-rich diet to be used in the chemoprevention and chemointervention of silica-accelerated nephritis in a mouse lupus model.

描述（由申请人提供）：自身免疫性疾病是由免疫系统攻击人体自身组织引起的一系列慢性致残性疾病，据估计对美国多达 2500 万人产生不利影响。自身免疫性疾病的患病率受到显着影响受环境因素（例如有毒物质暴露）和生活方式选择（例如饮食）的影响。值得注意的是，患系统性红斑狼疮 (狼疮) 是一种典型的自身免疫性疾病，影响 30 万美国人，通常与肾小球肾炎和肾衰竭有关，职业接触二氧化硅（例如采矿、建筑、保管和制造行业）会增加患系统性红斑狼疮 (狼疮) 的风险。研究表明，食用鱼油中的 n-3 多不饱和脂肪酸 (PUFA) 有望预防和改善包括自身免疫性肾炎在内的慢性炎症性疾病。这里的具体目标是检验以下假设：摄入 n-3 PUFA 会抑制狼疮易发小鼠的二氧化硅加速肾炎，并且这与肾脏中白细胞募集和炎症相关基因表达的减少相对应。这项研究将实现两个目标。在目标 1 中，将确定 n-3 PUFA 的消耗量及其如何影响二氧化硅加速狼疮性肾炎的潜伏期和严重程度。在目标 2 中，将测试 n-3 PUFA 如何调节现有二氧化硅加速狼疮肾炎的进展。与 NIEHS 的使命一致，这些目标的预期成果将是加深对 n-3 PUFA 如何影响二氧化硅引发和恶化自身免疫性肾炎的了解。这些发现将产生积极影响，因为这将是预测 n-3 PUFA 消耗如何预防或改善二氧化硅和其他毒物加速自身免疫的第一步。这项研究的贡献预计将有助于更好地了解 n-3 PUFA 消耗如何抵消二氧化硅引发和恶化的狼疮性肾炎。这一贡献意义重大，因为它将是导致营养学研究连续体的第一步 减轻环境触发和自身免疫恶化的策略。 这种预防和改善策略的可用性将使职业接触二氧化硅的个人能够 1) 降低患狼疮和其他自身免疫性疾病的风险，以及 2) 通过饮食和/或补充剂增加 n-3 PUFA 消耗来延缓现有自身免疫性疾病的进展。此外，n-3 PUFA 化学预防和化学干预可能同样适用于因接触石棉、重金属、三氯乙烯和农药等有毒物质而面临自身免疫风险增加的工人。最后，预计这些研究将揭示 n-3 PUFA 消耗对二氧化硅引起的肺病和纤维化的额外潜在益处，这是另一个尚未研究的领域。 公共卫生相关性：对于 NIH 和其他 PHS 机构的申请，本附件将反映项目摘要的第二部分。项目摘要/摘要（即“描述”）的第二个组成部分是相关性。使用不超过两三个句子来描述这项研究与公共卫生的相关性。在本节中，要简洁并使用一般外行观众可以理解的简单语言。系统性红斑狼疮 (狼疮) 是一种因身体产生针对自身的抗体和破坏性分子而引起的自身免疫性疾病，据估计影响 30 万美国人，其中大约一半患有肾炎，这是一种使人衰弱的疾病，可能导致丧失生命力。肾功能。在建筑、采矿、农业和制造业等常见职业中接触二氧化硅（地球上最丰富的元素）会增加个人患狼疮的风险。根据最近的证据，表明食用二十二碳六烯酸（DHA）（鱼油中常见的食物成分）与预防和改善自身免疫性肾炎有关，我们建议研究富含 DHA 的饮食在化学预防和化学干预中的潜力小鼠狼疮模型中二氧化硅加速肾炎的研究。