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造成的慢性疾病的星座，估计会对美国产生不利影响2500万人，自身免疫性疾病的普遍性受到自身免疫性疾病的普遍性影响，从而受到环境因素（例如，毒素的eacteant exteles and Lifesess）和饮食（E.G）的选择。值得注意的是，发展系统性红斑狼疮（狼疮）的风险是一种典型的自身免疫性疾病，影响了30万美国人，并且通常与肾小球肾上腺炎和肾衰竭有关，通过职业暴露会增加（例如，采矿，建筑，托管和制造工业）到硅粉。研究表明，鱼油中发现的N-3多不饱和脂肪酸（PUFA）的消费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。这里的具体目的是检验以下假设：N-3 PUFA的消耗将抑制狼疮易鼠的小鼠硅藻炎的肾炎，这将与肾脏中白细胞募集和与炎症相关的基因表达降低相对应。这项研究将以两个目的完成。在AIM 1中，将建立N-3 PUFA消耗及其如何影响二氧化硅加速性狼疮肾炎的潜伏期和严重程度。在AIM 2中，将测试N-3 PUFA如何调节现有硅胶腹炎的进展。与NIEHS的任务一致，这些目标的预期结果将是对N-3 PUFA如何影响二氧化硅触发和加剧自身免疫性肾炎的一种了解。这些发现将产生积极的影响，因为这将是预测N-3 PUFA消耗如何防止或改善二氧化硅和其他有毒物质对自身免疫的加速的第一步。预计这项研究的贡献将是对N-3 PUFA消费如何抵消二氧化硅肾炎触发和加剧的一种改进的理解。这项贡献很重要，因为它将是研究连续体的第一步，该研究将导致营养 减轻环境触发和加剧自身免疫性的策略。 这种预防性和改善策略的可用性将使二氧化硅在职业上接触到1）降低其患狼疮和其他自身免疫性疾病的风险，以及2）延迟通过饮食和/或补充来增加N-3 PUFA消费量来延迟现有自身免疫性的发展。此外，N-3 PUFA化学预防和化学干预可能会类似地应用于从暴露到毒物，例如石棉，重金属，三氯乙烯和农药等自身免疫风险的工人。最后，预计这些研究将揭示N-3 PUFA消耗对二氧化硅诱导的肺部疾病和纤维化的额外益处，这是另一个正在研究的区域。 公共卫生相关性：对于NIH和其他PHS机构申请，该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的。使用不超过两个或三个句子，描述这项研究与公共卫生的相关性。在本节中，要简洁并使用普通的语言，可以由一般的外行受众理解。据估计，全身性狼疮红斑（狼疮）是人体产生针对自我和破坏性分子的抗体产生的自身免疫性疾病，据估计会影响30万美国人，其中大约一半的人患有这些肾炎，这是一种衰弱的疾病，可能导致肾脏功能丧失。地球上最丰富的元素暴露在建筑，采矿，著名和制造等常见职业中会增加个人患狼疮的风险。基于最新的证据，将鱼油中常见的食品成分（DHA）的消耗联系起来，以预防和改善自身免疫性肾炎，我们建议研究富含DHA的饮食的潜力，用于用于化学上的化疗和化学干扰和化学粉状的硅粉 - 粉状型niNepererated Ninephrupus模型。