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(http://www.niehs.nih.gov//portfolio/index.cfm?do=portfolio.grantdetail&&grant_number=R01ES031082&format=word)
| Principal Investigator: Baccala, Roberto G | |
|---|---|
| Institute Receiving Award | San Diego Biomedical Research Institute |
| Location | San Diego, CA |
| Grant Number | R01ES031082 |
| Funding Organization | National Institute of Environmental Health Sciences |
| Award Funding Period | 01 May 2021 to 30 Apr 2025 |
| DESCRIPTION (provided by applicant): | Project Summary Systemic lupus erythematosus (SLE), the prototypic systemic autoimmune disease, is characterized by immune system hyperactivation, autoantibody production, and multiorgan inflammation. Although genetic predisposition is critical for disease expression, the low concordance rate in monozygotic twins (<40%) suggests the essential contribution of additional factors, mostly provided through environmental exposures. Indeed, significant epidemiological evidence has linked SLE and other systemic autoimmune disease to crystalline silica exposure but also to certain viral infections. Considering the critical role of innate immune activation in systemic autoimmunity, we hypothesized that silica inhalation, virus infection, and genetic predisposing factors synergize by activating distinct innate immunostimulatory pathways, that together lead to more efficient break of tolerance, earlier disease onset, and more severe autoimmune manifestations. In support of this hypothesis, we provide preliminary evidence that silica and virus exposures more effectively induce autoimmune manifestations in mouse models of lupus when given in combination than when given individually. Here we will use this experimental system to define the mechanistic basis of the interplay between virus infection and silica, including the temporal requirements of silica exposure and virus infection, the contribution of innate inflammatory pathways differentially induced by silica and virus, and roles of these factors in breaking immunological tolerance. |
| Science Code(s)/Area of Science(s) |
Primary: 53 - Autoimmunity Secondary: 03 - Carcinogenesis/Cell Transformation |
| Publications | No publications associated with this grant |
| Program Officer | Michael Humble |