CGRP IN SUBARACHNOID HEMORRHAGE

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DESCRIPTION Release of calcitonin gene-related peptide (CGRP) from trigeminal sensory fibers is a potent vasodilator mechanism in the cerebral circulation. Studies in experimental animals and patients have demonstrated that perivascular CGRP is depleted after subarachnoid hemorrhage (SAH). CGRP depletion after SAH suggests that an important compensatory vasodilator mechanism may be exhausted, which may contribute to susceptibility to vasospasm after SAH. The overall objective of these studies is to obtain insight into the regulation and function of CGRP following SAH. The first major goal is to identify the molecular mechanisms that control CGRP levels in trigeminal neurons following SAH. Studies are proposed to test the hypothesis that long-term depletion of perivascular CGRP is due to an inhibition of CGRP biosynthesis. CGRP peptide and mRNA levels will be measured in trigeminal ganglia cell bodies, and related to changes in the activity of the CGRP promoter. Promoter activity in trigeminal neurons in vivo will be measured using an adenoviral beta-galactosidase reporter vector. The second major goal of this project is to explore a novel therapeutic approach to prevent vasospasm after SAH. Vasospasm is a common and devastating complication of SAH, and a variety of therapeutic approaches have failed. CGRP is a reasonable candidate for gene therapy since vasodilator responses to CGRP are preserved or enhanced after SAH, in contrast to diminished responses to several other cerebral vasodilators. Studies are proposed to test the hypothesis that CGRP gene transfer can restore cerebral vascular function after SAH. Experiments will be performed using a novel adenoviral vector both in vitro with vascular ring preparations and in vivo following SAH. This project brings together investigators with expertise in cerebral circulation and CGRP gene regulation. Insight into regulation of CGRP gene expression may facilitate treatment, including gene therapy, for prevention of cerebral vasospasm after SAH.