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(http://www.niehs.nih.gov//portfolio/index.cfm?do=portfolio.grantdetail&&grant_number=R21ES035969&format=word)
| Principal Investigator: Ashwood, Paul | |
|---|---|
| Institute Receiving Award | University Of California At Davis |
| Location | Davis, CA |
| Grant Number | R21ES035969 |
| Funding Organization | National Institute of Environmental Health Sciences |
| Award Funding Period | 01 May 2024 to 30 Apr 2026 |
| 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 significant 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 - including immune conditions such as allergies and asthma - and an increased risk of having a child with ASD. Acute exacerbations are common in pregnant asthmatic women, with as many as 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. This is particularly concerning given the increasing presence of particulate matter from wildfires, which are becoming more frequent and severe. Despite this, the consequences of gestational exposure to maternal asthma/allergy- mediated responses, wildfire particulate matter (WPM), or their combined effects on fetal development remain largely unknown. We recently developed a preclinical model of maternal allergic asthma (MAA) during gestation that alters neurobiology and microglial function and disrupts epigenetic mechanisms in 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 altered microglia activation and function and that these exposures lead to epigenetic modifications of microglia that will enable us to discover gene pathways that diverge or converge between the two exposures. The proposed studies will examine WPM alone and the exacerbating effects of WPM sampled from the Northern California region during fire season plus MAA on microglia activation and function (Aim #1). Environmental exposures during critical windows in early life can impact epigenetic mechanisms, and the developing brain is particularly susceptible to these changes. Over-activation of the maternal immune system, for instance, can lead to an over-activation of the fetal immune system, potentially hindering brain development. We will test the hypothesis that epigenetic mechanisms in microglia are altered by combined WPM + MAA (Aim #2). If successful, this research will validate the concept that neurodevelopmental disorders such as ASD is, for some, caused by environmental contaminants that alter immune mechanisms. Our findings could 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 | No publications associated with this grant |
| Program Officer | Cindy Lawler |