Project Detail
Interagency Autism Coordinating Committee (IACC) logo
Office of Autism Research Coordination (OARC) logo

Redox abnormalities as a vulnerability phenotype for autism and related alterations in CNS development  

Evidence from multiple laboratories indicates that children with autism spectrum disorders (ASD) have a more oxidized metabolic status than normal children. Functionally, this means that when autistic children are exposed to environmental toxicants, they are more vulnerable to toxicity because they are less able to detoxify these exposures. Oxidative stress also can disrupt the normal development of the brain and the immune system and may contribute to the risk of developing autism. Evidence of oxidative stress has been far more frequently observed than any of the genetic differences that are associated with ASD, indicating that these metabolic alterations are a consistent and basic aspect of ASD. Despite the multiple theoretical insights raised by the observations of a more oxidized status in children with ASD, however, there is very little direct evidence that these differences are relevant to the understanding of these syndromes, and particularly to the neurological and immunologic components of ASD. Nor is it yet known whether the observation of oxidative abnormalities in peripheral blood cells or body fluids provides information regarding oxidative balance in the cells of the brain. The present studies bring together leading laboratories in the analysis of oxidative abnormalities in children with ASD, in the analysis of the role of oxidation in regulating the function of cells of the developing central nervous system (CNS), and in the development of robust and inexpensive sensor devices with the potential of greatly enhancing our ability to study oxidative biology in clinical settings. The studies of Project 1 will investigate the functional impact of oxidative stress in autistic children and determine whether metabolic biomarkers of oxidative stress can be used to develop a biochemical test that could identify children at risk of developing autism. Because autism is diagnosed solely on behavioral characteristics, a biochemical test for autism would allow doctors to identify at-risk children much earlier and would also provide a target for treatment that could improve the health and behavior of autistic children. Specifically, we will determine whether the abnormal metabolic profile can be used to identify children with regressive autism or at risk of developing autism so that treatment to improve their oxidized status can be initiated very early and possibly delay or prevent the progression into autism. Project 1 will also determine whether treatment to restore normal oxidative metabolism will also improve their behavior and/or immune function so that they will be able to better detoxify environmental exposures and resist infection. The studies in Project 2 will directly test the hypotheses that abnormalities in oxidative regulation observed in peripheral blood cells are predictive of abnormalities in cells of the developing brain, that such abnormalities cause developmental changes capable of explaining the abnormalities in myelination observed in children with ASD and also cause enhanced vulnerability to physiological stressors. In this context, our preliminary studies have already shown, among other findings, that the oxidative status of macrophages of the peripheral blood is predictive of the oxidative status of cells of the developing brain, providing the first demonstration that oxidative abnormalities detected by analysis of peripheral blood cells provides information on the developing central nervous system. Our previous studies on the role of oxidative regulation in the development of the myelin-forming cells of the brain suggest that such changes may be central to understanding the abnormalities in myelination associated with ASD. Our studies also show that increased oxidative status in cells of the developing brain is associated with increased vulnerability of these cells to physiological stressors. Finally, the studies of Project 3 address the challenge of providing new instrumentation that will enable the redox analyses of Projects 1 and 2 to be conducted at greatly reduced cost and with instrumentation that does not require extensive specialized training to utilize. The combined efforts of these three laboratories will provide new insights into the functional and mechanistic implications of oxidative imbalance in autism and will provide new options for earlier detection, treatment strategies, greater understanding of abnormal brain development, and new tools able to greatly extend current abilities to detect and analyze these alterations in a clinical setting. These studies will provide novel experimental insights into the potential contributions of oxidative abnormalities to ASD pathogenesis, improved means of detecting such abnormalities in a manner that will allow early identification of children with greater levels of vulnerability to environmental insults, and also of monitoring the effects of metabolic/dietary therapies, and identification of the molecular mechanisms that may provide rational targets for the development of therapeutic interventions. In addition, our studies also offer the opportunity of identifying strains of existing mice that may serve as experimental models for analyzing the neurological consequences of the oxidative abnormalities associated with ASD. Project Status
ONGOING

2010

Funder Department of Defense
Fiscal Year Funding $0.00
Current Award Period 2008-2010
Project Number AS073218P1
Principal Investigator James, Sandra
Received ARRA Funding? No
Strategic Plan Question Question 2: How Can I Understand What Is Happening? (Biology)
Subcategory Immune/Metabolic Pathways
Strategic Plan Objective Green dot: Objective has greater than or equal to the recommended funding. 2SA. Support at least four research projects to identify mechanisms of fever, metabolic and/or immune system interactions with the central nervous system that may influence ASD during prenatal-postnatal life by 2010. IACC Recommended Budget: $9,800,000 over 4 years. (Fever studies to be started by 2012.)
Federal or Private? Federal
Institution Arkansas Children's Hospital Research Institute
State/Country Arkansas
Web Link 1 Redox abnormalities as a vulnerability phenotype for autism and related alterations in CNS development (External web link)
Web Link 2 No URL available.
Web Link 3 No URL available.
New! History/Related Projects Redox abnormalities as a vulnerability phenotype for autism and related alterations in CNS development | $0.00 | 2010 | AS073218P2
Redox abnormalities as a vulnerability phenotype for autism and related alterations in CNS development | $0.00 | 2010 | AS073218
Redox abnormalities as a vulnerability phenotype for autism and related alterations in CNS development | $0.00 | 2009 | AS073218P2
Redox abnormalities as a vulnerability phenotype for autism and related alterations in CNS development | $0.00 | 2009 | AS073218P1
Redox abnormalities as a vulnerability phenotype for autism and related alterations in CNS development | $0.00 | 2009 | AS073218