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Principal Investigator: Pollard, Kenneth Michael
Institute Receiving Award Scripps Research Institute, The
Location La Jolla, CA
Grant Number R01ES029581
Funding Organization National Institute of Environmental Health Sciences
Award Funding Period 15 Aug 2018 to 31 Dec 2023
DESCRIPTION (provided by applicant): Silica exposure is associated with different disorders including pulmonary silicosis and autoimmune diseases such as progressive systemic sclerosis (Pss), systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and dermatomyositis (DM). Although a number of studies have noted the association of silica exposure with nephropathy, particularly in the setting of silica-induced autoimmunity, nothing is known about the genetics of silica-induced renal disease. This identifies a critical barrier to progress in understanding how silica exposure leads to autoimmune pathology. Kidney disease is a common feature in autoimmunity particularly in SLE where 30–60% of adults may have lupus nephritis. A number of features appear to be implicated including inflammation initiated by deposition of autoantibody containing immune complexes, leading to production of inflammatory mediators involving the innate and adaptive immune responses which results in cellular infiltrates, particularly of macrophages, progression to tissue damage, aberrant tissue repair and fibrosis. Studies, predominantly in animal models, have identified numerous molecular mediators that affect glomerulonephritis (GN). However, most play roles in innate and/or adaptive immunity and do not primarily dictate renal disease. Moreover, genetic studies in mice have identified a number of GN susceptibility loci, but many of these also associate with autoantibody production arguing against a primary role in nephritis. Studies of silica-induced autoimmunity and related pathology have been hampered by the lack of suitable animal models. To address this deficiency, we have begun to characterize the spectrum of immunological responses leading to autoimmunity in Diversity Outbred (DO) mice. We have examined the immunological responses to silica including the inflammatory response in the lung and associated protein biomarkers in the BAL fluid, the spectrum of serum autoantibodies and tissue pathology in the kidney. These findings have revealed significant development of silicosis, autoimmunity and glomerulonephritis (GN). Quantitative trait locus (QTL) analysis determined the latter to be linked with a region on chromosome 15. Significantly, this locus (called Smgn1) is associated with susceptibility and resistance to silica-induced GN. None of the DO mice carrying the A/J allele at the locus developed GN suggesting a dominant inheritance trait. We proposed two distinct but interrelated aims to further characterize the genetic elements involved in the development of GN. Aim 1: Identification of the mode of resistance to silica-induced glomerulonephritis. Aim 2: Identification of the mode of susceptibility to silica-induced glomerulonephritis. These studies are of considerable importance because they will allow insight into the molecular and cellular pathways leading to glomerulonephritis following silica exposure. Such information will be essential for identification of potential therapeutic targets as well as improving our understanding of kidney disease within the context of autoimmunity.
Science Code(s)/Area of Science(s) Primary: 53 - Autoimmunity
Secondary: -
Publications See publications associated with this Grant.
Program Officer Michael Humble
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