Involvement of opiorphins and polyamine synthesis in the development of priapism

DESCRIPTION (provided by applicant): Priapism is a disease which affects several thousand men in the US and millions worldwide, for which there is no pharmacological treatment. The mechanisms involved in the development of priapism are complex, and not well understood. A recent paper by my group describes a mechanism for the development of priapism which offers the potential to develop novel pharmacological approaches for its treatment. The over- expression of genes encoding Opiorphins (Vcsa1 in the rat and ProL1 and hSMR3A/B in humans) in the corpora of retired breeder rats will result in a priapic-like condition. We recently reported that over-expression of Opiorphins in corporal tissue of retired breeder rats results in the up-regulation of arginine catabolism through activation of ornithine decarboxylase (ODC) and polyamine synthesis. An ODC inhibitor (1,3-diaminopropane) when added to the drinking water of rats treated with plasmids over-expressing Opiorphins it can prevent the priapic-like condition. In a well established animal model for priapism (the Berkley sickle cell mice, BERK mice) we have demonstrated that in corporal tissue there is elevated expression of mSMR2 (the mouse Opiorphin homologue) prior to the onset of a priapic-like condition. Onset of the priapic-like condition in mice is accompanied by higher levels of mSMR2 expression and the up- regulation of key enzymes in polyamine metabolism (arginase I and II and ODC). Our evidence suggests that the up-regulation of Opiorphins and the polyamine synthetic pathway may play a role in the development of priapism associated with sickle cell disease and interventions targeting the polyamine synthetic pathway maybe useful in preventing priapic-like pathologies in men with sickle cell disease. The goal of this proposal is to test the hypothesis that increased levels of Opiorphin expression in the corpora of animals with sickle cell disease modulates arginine catabolism and polyamine synthetic pathways and thereby plays a role in the development of priapism. Inhibition of Opiorphin expression or the polyamine synthetic pathways may represent targets for treating priapism. If our research demonstrates a role for Opiorphins and polyamine synthesis in the development of priapism associated with sickle cell disease, not only will this identifying novel pharmacological targets but also biomarkers for determining which patients are at risk of developing priapism. PUBLIC HEALTH RELEVANCE: Priapism, a prolonged erection without sexual stimulation, potentially leads to irreversible damage of the corporal tissue and erectile dysfunction. It is associated with several conditions but is particularly prevalent in men with sickle cell disease where its incidence is about 40%. At present there is no adequate pharmacological intervention for its treatment. The work we propose here will investigate the role of Opiorphins and polyamine synthesis in priapism, potentially identifying novel pharmacological targets for its treatment as well as identifying biomarkers for determining which patients are at risk of developing priapism.