reproduced verbatim): Maternal drug abuse places hundreds of thousands of progeny at risk each year in the United States. This problem has become more severe recently, due to the greater availability of purer heroin and an increase in young abusers. The effect of opioids on mitogenic pathways in the fetus of drug-addicted mothers may contribute to the physiological and psychological delays observed in their offspring. Glial cell proliferation plays an integral role in normal brain development. Opioids modulate mitogenic signaling in astrocytes from developing brain. The broad goal of our research is to delineate mechanisms involved in opioid modulation of mitogen-mediated glial cell growth and differentiation. Our previous studies disclosed major features of the mechanism of the mitogenic action of an agonist of the endogenous kappa OR in C6 glioma cells, an astrocytic model system. Evidence for both receptor endocytosis-dependent and -independent opioid mitogenic signaling has been discovered. The particular focus of this application is to delineate how and where in the cell opioid and RTK signaling converge to modulate proliferation of primary astrocytes from perinatal brain of various ages. There are three specific aims:
AIM 1) Identify the point of convergence between opioid and mitogenic signaling pathways upstream of the MAP kinase cascade in primary astrocytes.
AIM 2) Test the hypothesis that opioid receptor internalization is required to """"""""switch"""""""" opioid signal transduction to a MAP kinase-modulating mode for mitogens.
AIM 3) Test the hypothesis that mitogenic signaling component(s) are desensitized upon chronic exposure to opioids that attenuate mitogen-induced proliferation of astrocytes. We will use biochemical, immunological, recombinant protein and other molecular biological techniques to study opioid signaling in primary astrocytes. The answers sought in these mechanistic studies have fundamental significance, and also bear on the important public health problem of maternal drug abuse. They may also have implications for understanding some aspects of AIDS dementia.
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