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(http://www.niehs.nih.gov//portfolio/index.cfm?do=portfolio.grantdetail&&grant_number=R21ES035492&format=word)
| Principal Investigator: Ashwood, Paul | |
|---|---|
| Institute Receiving Award | University Of California At Davis |
| Location | Davis, CA |
| Grant Number | R21ES035492 |
| Funding Organization | National Institute of Environmental Health Sciences |
| Award Funding Period | 10 Aug 2023 to 31 Jul 2025 |
| DESCRIPTION (provided by applicant): | Project Summary/Abstract: Autism spectrum disorders (ASD) are pervasive, highly prevalent lifelong disorders for which pharmacological interventions are not readily available. While genetic factors are likely contributors to these disorders, heritability estimates indicate strong environmental contributions. Of particular interest is the link between fetal gestation and the activation of the maternal immune system during critical periods of development. Epidemiological reports suggest a strong association between periods of maternal immune activation and an increased risk of having a child with ASD including immune conditions such as allergies and asthma. Unique immune cascades representative of asthma and allergy responses have been detected in amniotic fluid and maternal serum mid pregnancy of mothers whose child was later diagnosed with ASD. Acute exacerbations are common in pregnant asthmatic women with as many 35% suffering attacks requiring hospitalization. In addition, particulate matter from air pollution, a major exacerbating factor in allergic asthma, has been linked with an increased risk for ASD. Wildfire activity, a significant producer of particulate matter, is increasing in size, severity, frequency, duration of fire season and areas of susceptibility. However, little is known about the consequences of maternal asthma/allergy mediated responses, wildfire particulate matter (WPM), or their combined effects on fetal development. We have described the first set of preclinical studies to test the hypothesis that maternal allergic asthma (MAA) induced during gestation imparts alterations in brain neurobiology and functional behavioral outcomes in the offspring. We have WPM samples collected in situ and through proximity sampling of wildfire emissions, capturing the complexity of real-world complex WPM exposures. We will test the innovative hypothesis that WPM and MAA combined are causally linked to severe impaired behavioral endpoints that have a high degree of face validity for neurodevelopmental disorders (NDD) and ASD-relevant symptoms, and that these exposures lead to epigenetic modifications of microglia. The proposed studies will examine WPM alone and the exacerbating effects of WPM sampled from Northern California region during fire season and MAA on behavioral outcomes (Aim #1). Pregnancy is a time when epigenetic changes help a static genome adapt to the maternal environment, so that if the maternal immune system is overly activated, the fetal immune system will also be over activated at the expense of brain development. We will test the hypothesis that epigenetic mechanisms control microglia responses in the fetus following WPM + MAA (Aim #2). If successful, this research will validate the concept that NDD is, for some, a disorder due to the direct effects of common environmental contaminants on immune mechanisms that will identify novel mechanisms and preventative strategies for one of the most visible public health concerns of our time. |
| Science Code(s)/Area of Science(s) |
Primary: 61 - Neurodevelopmental Secondary: 03 - Carcinogenesis/Cell Transformation |
| Publications | See publications associated with this Grant. |
| Program Officer | Cindy Lawler |