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(http://www.niehs.nih.gov//portfolio/index.cfm?do=portfolio.grantdetail&&grant_number=R01ES035813&format=word)
| Principal Investigator: Thompson, Christopher Kirk | |
|---|---|
| Institute Receiving Award | Virginia Polytechnic Inst And St Univ |
| Location | Blacksburg, VA |
| Grant Number | R01ES035813 |
| Funding Organization | National Institute of Environmental Health Sciences |
| Award Funding Period | 15 Apr 2024 to 28 Feb 2029 |
| DESCRIPTION (provided by applicant): | Project Summary Lead (Pb) poisoning is a persistent health issue in the United States due to legacy contamination from Pb-based sources such as paint, plumbing, and gasoline. Children are most susceptible to Pb poisoning, which causes persistent cognitive deficits and low IQ. The specific mechanisms by which Pb poisoning impacts development are not fully understood, however. Previous research showed that Pb impacts several thyroid hormone (TH)-related processes, including decreases in expression of TH distributor proteins (THDPs) in the choroid plexus. This is an important issue because TH is a critical regulator of brain development; disrupted TH signaling in utero leads to smaller brain size and mental retardation. The impact of Pb-induced THDP impairment on development has not been fully tested. Given the impact of Pb on THDP expression, our central hypothesis is that Pb poisoning impairs TH distribution into the brain and compromises TH-dependent developmental mechanisms. TH regulates important aspects of brain development in both humans and amphibian, in some surprisingly similar ways. The overall rationale of this proposal is that TH is the key driver of metamorphosis in frogs, which makes tadpoles ideally suited to address how Pb dysregulates TH-dependent mechanisms of development. We will use Xenopus laevis tadpoles to assess the impact of Pb on the expression and function of THDPs in the choroid plexus and its effects on TH-sensitive cellular and molecular mechanisms brain development. The central hypothesis will be tested in three specific aims: 1) To determine the effects of Pb poisoning on expression of THDPs, TH-sensitive genes, neurogenesis, neuronal differentiation, and spine maturation using time-lapse in vivo imaging techniques. 2) To test if knockdown of THDP expression in the choroid plexus mimics the effects of Pb poisoning. 3) To test if overexpression of THDPs in the choroid plexus can counter the effects of Pb-poisoning on TH- dependent mechanisms of brain development. The outcomes of this research will test a significantly understudied mechanism by which Pb is hypothesized to compromise development. These protocols will serve as a new, unique set of sensitive end points to evaluate not just heavy metals but any chemical suspected of disrupting THDP expression and function. This proposal is innovative because it uses advanced techniques that have not been previously used in animals to address the issue of developmental Pb neurotoxicity. This project is significant because it will conclusively test the degree to which Pb affects development via dysregulation of TH-signaling and therefore may lead to alternative/complimentary therapies for counteracting Pb-poisoning in children. |
| 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 |