This grant application represents in practice the competitive renewal of Dr. Ishikawa's R29 award that was not requested for renewal during the last review period. This has been a key source of funding for Dr. Ishikawa's laboratory and the productivity reflects this (see Previous Studies). This application requests for extension of previous work on mechanisms mediating cAMP signal by the type V adenylyl cyclase isoform, the major isoform in the heart and the striatum of the brain. This isoform was originally isolated in Dr. Ishikawa's laboratory and has been characterized in detail biochemically and genetically in the past years. One proposed aim that persists from the previous grant is elucidating the role of this isoform relative to that of the other isoforms, however, with two major modifications. We will characterize its role using a transgenic mouse model in which this isoform was disrupted. One hypothesis is that the unique property of this isoform is utilized in regulating the intracellular cAMP signal in striatal neurons, and is essential in maintaining the striatal function. We will investigate the changes in cAMP signal in the striatal neurons, which will be compared to those in the heart, as well as the alterations in motor functions, e.g., coordination and locomotion, in this animal model. Pharmacological treatment with selective dopaminergic receptor agonists and a strategy to transfer this adenylyl cyclase isoform gene into the striatum and the recovery of locomotor function will be explored. Another hypothesis is that it is feasible to pharmacologically regulate the activity of adenylyl cyclase in an isoform-specific manner. Instead of regulating cAMP signal at the level of the receptor, e.g., beta-adrenergic receptor blocker, targeting an adenylyl cyclase isoform may have an advantage of better organ-selectivity and therapeutical effectiveness; it may work even when the receptor is downregulated or desensitized. We will examine the pharmacological properties of various new compounds that may regulate the activity of type V adenylyl cyclase in an isoform-specific manner.
These aims and hypotheses will be tested by investigators with expertise in biochemistry, pharmacology, and physiology in intact animals, in vitro assays, proteomics and genomics.
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