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Grant Abstract

Grant Number: 5R21ES021265-02
PI Name: Pestka
Project Title: Dietary Lipids and Silica-Accelerated Autoimmunity

Abstract: 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

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