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(http://www.niehs.nih.gov//portfolio/index.cfm?do=portfolio.grantdetail&&grant_number=R01ES035851&format=word)
| Principal Investigator: Pitts, Matthew William | |
|---|---|
| Institute Receiving Award | University Of Hawaii At Manoa |
| Location | Honolulu, HI |
| Grant Number | R01ES035851 |
| Funding Organization | National Institute of Environmental Health Sciences |
| Award Funding Period | 09 Feb 2024 to 31 Dec 2027 |
| DESCRIPTION (provided by applicant): | PROJECT SUMMARY/ABSTRACT Mercury (Hg) is a known neurotoxin considered among the top ten chemicals of public health concern by the World Health Organization. While the acute effects of Hg are well chronicled, the consequences of chronic, low-dose exposure are less clear. Given that clinical symptoms of most psychiatric disorders do not emerge until early adulthood, there is a critical need for better understanding of the neural cell types and circuits most adversely impacted by adolescent Hg exposure, as well as the associated behavioral phenotypes. At the molecular level, Hg irreversibly binds to catalytic selenium (Se) moieties present in antioxidant selenoenzymes, leading to redox dysregulation, altered Ca2+ homeostasis, and mitochondrial dysfunction. Growing evidence indicates that oxidative stress impedes maturation of GABAergic circuitry, resulting in a permanent imbalance between excitatory and inhibitory neurotransmission. Moreover, among GABAergic cell types, fast-spiking, parvalbumin-expressing interneurons (PVIs) are most acutely impacted by redox imbalance. The long-term goal of this project is to better understand how interactions between Hg exposure and dietary Se status influence maturation of excitatory-inhibitory balance and the risk of developing psychiatric disorders. Our central hypothesis is that Hg-mediated inhibition of selenoenzyme activity during adolescence preferentially impairs PVIs, leading to irreversible deficits in excitatory-inhibitory tone and behavior. Our research team has expertise to definitively assess the effects of altered Se metabolism on molecular, immunohistological, and behavioral indices in rodents, with innovative tools and assays established to successfully perform the proposed studies. Our two specific aims are as follows: Aim #1: Determine the effects of Hg on Se-dependent redox balance, excitatory-inhibitory tone, and electrophysiological activity in primary cortical cultures. Aim #2: Characterize the immediate and long-term effects of subtoxic juvenile Hg exposure on brain, behavior, and gut microbiota. |
| Science Code(s)/Area of Science(s) |
Primary: 61 - Neurodevelopmental Secondary: 03 - Carcinogenesis/Cell Transformation |
| Publications | No publications associated with this grant |
| Program Officer | Jonathan Hollander |