Priapism is defined as prolonged penile erection occurring unassociated with sexual interest. 40% of male sickle cell disease patients display priapism. The disorder is dangerous and urgent given its association with erectile tissue damage and erectile dysfunction. Current strategies to manage the disorder are poor due to lack of fundamental understanding of the pathophysiology of priapism. Recently our laboratory unexpectedly observed spontaneous and prolonged penile erections in adenosine deaminase (ADA)-deficient mice. As a result of ADA deficiency these mice exhibit a widespread increase in adenosine, a signaling nucleoside that elicits many physiological effects by engaging membrane receptors. The priapism phenotype is associated with the accumulation of high levels of adenosine in the penes of ADA-deficient mice. Intraperitoneal injection of PEG-ADA (a modified form of ADA used for enzyme therapy) quickly reverses the priapic activity, suggesting that the erections are due to elevated levels of adenosine. In addition, ADA-deficient mice display a hypersensitive penile erection in response to cavernous nerve stimulation. Intracavernous injection of adenosine in wild type mice results in penile erection, an outcome that was more intense and more prolonged when adenosine was co-injected with an ADA inhibitor. Very recent findings indicate that adenosine induced priapism requires A2B receptor activation, an observation with obvious therapeutic implications. It is noteworthy that ADA-deficient mice are the only animal model of priapism characterized by spontaneous and prolonged penile erections and penile fibrosis. These features are similar to priapism seen in human. The utility of ADA-deficient mice as animal models of priapism is aided significantly by the ability to use PEG-ADA enzyme therapy as a convenient experimental strategy to regulate adenosine levels, and thereby control the penile abnormalities. Thus, an extensive amount of preliminary data indicate that ADA-deficient mice are a valuable animal model to investigate the role of adenosine signaling in priapism and penile fibrosis. To this end three specific aims are proposed.
In AIM I, we propose to use biochemical, pharmacological and genetic approaches to assess the significance of adenosine signaling in the priapism phenotype associated with ADA- deficient mice.
In AIM II, we propose to use histological and primary cell culture and organ culture approaches to identify the cell types responsive to the adenosine induced priapism seen in ADA-deficient mice.
In AIM III, we propose to investigate the possibility that the priapism seen in ADA deficient mice progresses to penile fibrosis and eventually to erectile dysfunction. ADA deficient mice provide an unprecedented opportunity to investigate the role of adenosine signaling in penile erection and priapism. The results of proposed research are likely to help to formulate prevention strategies and new therapies for the treatment of this condition. ABSTRACT (lay version) Priapism is defined as abnormal prolonged penile erection occurring unassociated with sexual interest. The disorder is dangerous and urgent given its association with immediate erectile tissue damage and eventual erectile dysfunction. Current strategies to manage the disorder are poor due to lack of fundamental understanding of the pathophysiology of priapism. Our laboratory recently has observed priapism in a line of mutant mice with a specific genetic defect. These mutant mice display features of priapism seen in humans, including prolonged penile erection and evidence of penile tissue fibrosis. As a result of the genetic defect these mice overproduce adenosine, a signaling molecule that elicits many physiological effects by activating specific receptors on the surface of cells. Our recent findings suggest that overproduced adenosine may be responsible for the priapism observed in these mutant mice. We propose to use these mutant mice as an animal model to investigate the role of adenosine signaling in priapism and penile fibrosis. This research will provide us with novel insight into mechanisms of adenosine signaling in penile erection, priapism and eventually, erectile dysfunction. By understanding the molecular events involved in the development of priapism, we seek to develop novel therapeutic strategies to treat this disease. ? ? ?
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