Grantee Research Project Results
The Role of Obesity in Biological Responses to Particulate Matter in Mice
EPA Grant Number: R836152C003Subproject: this is subproject number 003 , established and managed by the Center Director under grant R836152
(EPA does not fund or establish subprojects; EPA awards and manages the overall grant for this center).
Center: Center for the Study of Childhood Asthma in the Urban Environment
Center Director: Hansel, Nadia
Title: The Role of Obesity in Biological Responses to Particulate Matter in Mice
Investigators: Polotsky, Vsevolod Y , Mitzner, Wayne
Current Investigators: Polotsky, Vsevolod Y
Institution: The Johns Hopkins University
EPA Project Officer: Callan, Richard
Project Period: September 1, 2015 through August 31, 2019 (Extended to August 31, 2021)
RFA: Children's Environmental Health and Disease Prevention Research Centers (2014) RFA Text | Recipients Lists
Research Category: Human Health , Children's Health
Objective:
Specific Aim 1: Test causal links between obesity and particulate matter (PM)-induced airway hyperresponsiveness (AHR).
Specific Aim 2: Examine the role of sleep apnea using our novel model of upper airway obstruction during sleep induced by excessive tongue adiposity.
Specific Aim 3: Assess the effects of sleep apnea treatment on asthma control.
Approach:
Animal studies of Project 3 will complement human Projects 1 and 2 enabling us to examine these relationships mechanistically. We will 1) utilize established models of diet-induced obesity (DIO) and PM exposure in the non-atopic obesity-prone mouse strain C56BL/6J to identify the effect of obesity on the AHR; 2) examine the role of adipokines and inflammatory cytokines, especially IL-6; 3) examine the role of sleep apnea using our novel model of upper airway obstruction during sleep induced by excessive tongue adiposity; this unique model has been engineered by overexpressing an adipogenic transcription factor peroxisome proliferator-activated receptor gamma (PPARγ) in the tongue. The overarching hypothesis of the Project 3 is that obesity exacerbates the PM-induced AHR due to pathogenic effects of adiposity and comorbid sleep apnea and that the effects of obesity are mediated via IL-6. Furthermore, these detrimental effects of obesity can be attenuated by weight loss and sleep apnea treatment. In Specific Aim 1, we will test causal links between obesity and the PM-induced AHR and inflammation. (A) We will quantify the PM-induced AHR and inflammation in lean and DIO wildtype and IL-6 knockout mice; (B) To link to potential therapeutic actions, we will quantify the ability of weight loss to attenuate the PM-induced AHR and inflammation. In Specific Aim 2, we will examine effects of sleep apnea on the PM-induced AHR and inflammation. We will quantify the PM-induced AHR and inflammation in DIO mice with recurrent upper airway obstruction during sleep caused by genetically induced excessive tongue adiposity. Experiments will also assess the effects of sleep apnea treatment, which will be modelled by supplemental oxygen. Thus, Project 3 will complement human studies proposed in Projects 1 and 2 exploring the causal relationships between PM, obesity and sleep apnea in the development of AHR and airway inflammation.Rationale:
Children obesity, asthma and particulate matter (PM) exposure disproportionally affect low-income minority children in the US. Previous research from this group provided evidence that obesity may exacerbate effects of PM on asthma. The overall OBESE ASTHMA Program proposal focuses on the role of obesity in amplifying the pathogenic effects of PM on asthma in children. The underlying mechanisms by which obesity augments effects of PM are poorly understood. Preliminary data shows that obesity enhances PM-induced airway hyperresponsiveness (AHR) and increases IL-6 levels in the lungs. PM and obesity may interact leading to AHR and chronic airway inflammation. Obesity also predisposes to obstructive sleep apnea (OSA). OSA is highly associated with asthma in children and treatment of OSA improves asthma control. Environmental pollution is associated with OSA and reduction in air pollution decreases the severity of OSA. Thus, obesity and sleep apnea may interact with PM to exacerbate asthma.Progress and Final Reports:
Main Center Abstract and Reports:
R836152 Center for the Study of Childhood Asthma in the Urban Environment Subprojects under this Center: (EPA does not fund or establish subprojects; EPA awards and manages the overall grant for this center).
R836152C001 Investigating obesity as a susceptibility factor for air pollution in childhood
R836152C002 Novel exposure metrics for assessing the effects of ultrafine and fine particulate matter on asthma in children
R836152C003 The Role of Obesity in Biological Responses to Particulate Matter in Mice
The perspectives, information and conclusions conveyed in research project abstracts, progress reports, final reports, journal abstracts and journal publications convey the viewpoints of the principal investigator and may not represent the views and policies of ORD and EPA. Conclusions drawn by the principal investigators have not been reviewed by the Agency.