More About Our Research
The overarching goal of our research is to understand the molecular basis
of neurodevelopmental and neuropsychiatric disorders.
We are currently focused on developing a system to screen and identify
environmental chemicals that confer risk to Autism Spectrum Disorders
(ASDs). ASDs are a heterogenous group of neurodevelopmental disorders
defined by social abnormalities, language deficits, and repetitive
behaviors that currently afflicts 1 in 68 children in the United States
(U.S.). Autism costs society an estimated $126 billion per year in the
U.S. and the lifetime cost of providing care to each individual ranges
from $1.4 to $2.3 million, depending on the extent of intellectual disability.
There is evidence that suggests ASD can result when environmental factors
interact with specific genetic susceptibilities to disrupt brain development
during gestation. Environmental chemicals are one type of environmental
factor that poses risk for development of ASD.
Analysis of environmental chemicals is an onerous task because over 80,000 chemicals are in commercial use today, with thousands more introduced each year (most with inadequate toxicological data; http://ntp.niehs.nih.gov/). Making things even more complicated, hundreds of genetic variations (e.g., missing genes, mutations in genes, and increased copies of genes) are linked to ASD, so chemicals must also be tested in combination with many different genetic backgrounds.
We propose using the fruit fly, Drosophila melanogaster - proclaimed a “model of choice” for the advancement of risk assessment of developmental toxins by the National Research Council Committee on Toxicology - to screen for environmental chemicals that disrupt neural development in organisms with genetic changes linked to ASD. Drosophila were chosen in part because humans and fruit flies exhibit similar molecular responses to many drugs that act within the central nervous system. In addition, many fundamental cellular, developmental, and neurological mechanisms are analogous in humans and Drosophila. If a chemical affects a gene in Drosophila, and that gene is conserved in humans, the chemical will likely also affect humans. In fact, an estimated 75% of human disease-related genes are conserved in flies – meaning these genes have similar DNA sequences and similar biological functions in both humans and Drosophila. This includes a number of genes implicated in ASD that have been shown to impact neural development and adult behavior in Drosophila.
In addition to sharing genetic similarity with humans, Drosophila have a rapid generation time (approximately nine days from egg to adult), which enables quick generation of data. It is also relatively simple to modify genes in Drosophila, which is important for studying a disorder that may be caused by hundreds of different genetic mutations.
Our current studies, supported by a CSUPERB grant, involve exposing Drosophila fmr1 (fragile X mental retardation 1) mutants to polychlorinated biphenyl 95 (PCB-95). Mutations in fmr1 are thought to be the most prevalent single gene cause of ASD in humans and the role fmr1 plays in brain development is conserved from flies to humans. PCB-95 is a neurotoxicant known to exacerbate neural defects caused by fmr1 mutations in mammals. Using PCB-95 and Dfmr1 mutant flies, we are measuring behavioral, cellular, and molecular consequences of chemical exposure.
We hope this research will provide a set of parameters for future research to identify chemicals that confer risk for individuals carrying mutations in fmr1. The use of Drosophila could increase the pace of toxicological assessment and provide insight into preventative measures that could decrease the severity of or, in some cases, prevent ASD.
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