Dietary Lipids and Silica-Accelerated Autoimmunity

Summary

Principal Investigator: James J Pestka
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.
Funding Period: 2012-05-11 - 2015-03-31
more information: NIH RePORT

Detail Information

Research Grants30

  1. Role of Estrogen Receptors in Lupus-Modulators of the Inflammatory Response
    Gary S Gilkeson; Fiscal Year: 2013
    ..abstract_text> ..
  2. A critical role of TAM receptors in autoimmune nephritis
    Wenhai Shao; Fiscal Year: 2013
    ..Results from this study will extend our understanding of the mechanisms in which Mer and Axl regulate chronic inflammation and autoimmunity. Data may reveal potential therapeutic targets for lupus nephritis. ..
  3. Effects of miR-21 and miR-155 inhibition in SLE
    Marianthi Kiriakidou; Fiscal Year: 2013
    ..To our knowledge HITS-CLIP has not been previously performed in SLE and the combined results of HITS-CLIP and RNAseq will offer a panoramic view of all genes directly regulated by miRNAs in cells of the immune system in mouse lupus. ..
  4. Elucidating Risks: From Exposure and Mechanism to Outcome
    James A Swenberg; Fiscal Year: 2013
    ..This Program is highly relevant to Superfund by addressing high-priority chemicals and by focusing on mechanisms underlying health effects, exposure assessment, and remediation to mitigate exposure and toxicity. ..
  5. PAHs: New Technologies and Emerging Health Risks
    David E Williams; Fiscal Year: 2013
    ..Accomplishing these goals will provide significant scientific advancement and improve the quality of life for impacted communities. ..
  6. TOXIC SUBSTANCES IN THE ENVIRONMENT
    Martyn T Smith; Fiscal Year: 2013
    ..The program will be overseen and coordinated by an Administration core (A). ..
  7. Pacific Southwest RCE for Biodefense &Emerging Infectious Diseases Research
    Alan G Barbour; Fiscal Year: 2013
    ..abstract_text> ..
  8. Philadelphia Autoimmunity Center of Excellence
    A M Rostami; Fiscal Year: 2013
    ..The Clinical Component proposes novel clinical trial concepts and studies to understand the mechanisms of action of the therapeutics being tested. As such, they are an integral part of this ACE. ..