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ADHESION AND REPULSION MOLECULES IN DEVELOPMENTAL NEUROTOXIC INJURY
Impact/Purpose:
Normal brain development depends on the appropriate temporal and spatial expression of neural adhesion and repulsion molecules, several families of membrane proteins that provide instructive and permissive guidance for neuronal and neuritic movement. We postulate that neurotoxic metals perturb brain development/morphogenesis by disrupting the regulated expression and function of critical morphoregulatory adhesion and repulsion molecules. We further postulate that defects in these critical molecules give rise to morphological, biochemical, and behavioral effects of relevance to the study of autism spectrum disorder.
The objective of this research project is to address four specific questions: (1) Does exposure to neurotoxic metals alter the expression of adhesion and repulsion molecules during critical stages of brain development and thereby compromise morphogenesis? (2) Do selective transcriptional, translational, or post-translational processes mediate metal-induced changes in adhesion and repulsion molecules? (3) What are the behavioral consequences of toxicant-disturbed adhesion and repulsion molecules? (4) Can the deleterious effects of toxic metals on morphoregulatory molecules be modified or ameliorated by intervention strategies?
The studies utilize complementary biochemical and behavioral assessment to characterize the effects of toxic metals on neural cell adhesion molecules (NCAM), L-1, and the Eph family of tyrosine kinase repulsion molecules.
Description:
Work during the next year will focus on establishing structural and functional correlations between the changes in Eph/ephrin expression and MeHg exposure. We have begun to characterize the cellular expression of the specific molecules using in situ hybridization techniques. These results will be correlated with the structure of specific neural pathways (e.g., hippocamposeptal) using DiI labeling. The exact site of the dysregulation of Eph/ephrin RNA expression will be sought by examining the molecular machinery of RNA transcription. Working in collaboration with Dr. Wagner, we will examine further the relationship between the expression of morphoregulatory molecules and behavior, focusing on the effects on early-onset behaviors. We are particularly interested in expression of these molecules at the synapse, where their dysregulation would have immediate and persistent effects on the function of the brain.