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(http://www.niehs.nih.gov//portfolio/index.cfm?do=portfolio.grantdetail&&grant_number=R01ES004738&format=word)
| Principal Investigator: Laskin, Debra L | |
|---|---|
| Institute Receiving Award | Rutgers Biomedical And Health Sciences |
| Location | Piscataway, NJ |
| Grant Number | R01ES004738 |
| Funding Organization | National Institute of Environmental Health Sciences |
| Award Funding Period | 01 Jun 1989 to 30 Jun 2027 |
| DESCRIPTION (provided by applicant): | ABSTRACT Ozone is a ubiquitous air pollutant and the main component of photochemical smog. It remains a federally regulated air pollutant of ongoing public health concern. Inhaled ozone irritates and damages the lung in both healthy and susceptible individuals, including children and the elderly. Ozone causes inflammation and constriction of the airways, reducing pulmonary function. Ozone also exacerbates asthma and chronic lung disease. Thus, elucidating mechanisms of toxicity is highly relevant in terms of identifying new strategies to reduce lung injury from ozone and potentially other air pollutants. Our studies are focused on macrophages, which we have demonstrated play a key role in both initiating and resolving inflammatory responses to ozone- induced tissue injury. These activities are mediated by distinct subsets broadly classified as proinflammatory M1 and proresolution M2 macrophages. Effective resolution of inflammation following tissue injury depends on metabolic reprogramming of macrophages from an M1 phenotype to an M2 phenotype, which involves a switch from glycolysis to oxidative phosphorylation as a source of energy. We discovered that this reprogramming is suppressed following ozone exposure. The goal of our studies is to analyze mechanisms underlying suppression of macrophage reprogramming. In recent studies we identified farnesoid-X receptor (FXR), a nuclear receptor important in regulating lipid metabolism, with anti-inflammatory activity, as central to promoting M1 to M2 macrophage reprogramming in the lung. Following ozone exposure, macrophage FXR activity is downregulated. This is associated with increased activity of proinflammatory M1 macrophages and reduced activity of proresolving M2 macrophages. We also found that microRNAs that regulate the proinflammatory transcription factor NFκB are dysregulated in macrophages after ozone exposure. As a consequence, there is protracted activation of NFκB signaling resulting in increased production of inflammatory mediators. We hypothesize that these mediators suppress FXR activity which prevents activation of the PPARγ coactivator (PGC-1β), an inducer of macrophage M1 to M2 metabolic reprogramming. To test this hypothesis, we will perform parallel studies in mice and humans and (1) Determine if persistent inflammation following ozone exposure and lung injury is due to impaired development of proresolution M2 macrophages, and assess whether this is caused by protracted activation of NFκB; (2) Analyze the role of FXR and its target, PGC-1β in the development of proresolution M2 macrophages in the lung following ozone exposure; and (3) Assess whether protracted activation of NFκB is a consequence of ozone-induced alterations in microRNAs regulating NFκB. Results of these studies will provide new mechanistic insights into ozone toxicity. This will have significant translational implications for the development of new strategies for preventing and treating the toxicity of ozone, and possibly other agents that induce inflammatory lung injury. |
| Science Code(s)/Area of Science(s) |
Primary: 69 - Respiratory Secondary: 00 - Use when there is no secondary code assigned |
| Publications | No publications associated with this grant |
| Program Officer | Srikanth Nadadur |