This application has two long-range goals. The first is to advance our understanding of cellular and molecular functions of cysteine string proteins (csps). Csps are a family of proteins associated with secretory organelles in nerve cells and elsewhere. The second is to pursue recent findings which indicate that lithium (Li) ions modulate csp gene expression in vitro and in vivo. While the first goal entails basic investigations of the role of csps in secretion, the latter goal is likely to have more- immediate clinical relevance. This is because Li, which is used in the management of bipolar-affective disorders, remains a mechanistic enigma. Thus, further study of the LI-csp link may afford insights into the therapeutic role of Li, as well as into the cause and improved treatment of bipolar syndromes. To approach these long-term goals, the current proposal has three specific aims: First, we will study regulatory, and functional/anatomical correlates of Li's effect on csp gene expression. These investigations will illuminate the signaling pathways that mediate this effect of Li, and also suggest whether Li is likely to modify the secretory behavior of discrete populations of neurons in the brain. Second, we propose to characterize further the secretory functions of a unique relative of csp. It is our hypothesis that this protein substitutes for csp in csp null mutant fruit flies. Using genetic, biochemical and physiological strategies, we plan to evaluate the role of this """"""""csp substitute"""""""" in wild type and csp mutant Drosophila, as well as in vertebrates. Finally, we plan to exhibit calcium-ion independent regulated secretion of cortical granules. Perturbation of csp function in this system will afford insight into molecular contributions of csps to regulated secretion. Taken together, these aims constitute substantial progress toward resolving the role of csps in normal and pathological circumstances.
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