Involvement of opiorphins and polyamine synthesis in the development of priapism

描述（由申请人提供）：阴茎勃起障碍是一种影响美国数千名男性和全球数百万男性的疾病，目前尚无药物治疗方法。阴茎勃起症发生的机制是复杂的，还没有被很好地理解。我的小组最近发表的一篇论文描述了阴茎勃起障碍的发展机制，这为开发新的药物治疗方法提供了潜力。在退休的繁殖大鼠体内，编码Opiorphins的基因（大鼠的Vcsa1和人的ProL1和hSMR3A/B）的过度表达会导致类似priapic的情况。我们最近报道了Opiorphins在退休繁殖大鼠的身体组织中的过度表达，通过激活鸟氨酸脱羧酶（ODC）和多胺合成导致精氨酸分解代谢上调。将ODC抑制剂（1,3-二氨基丙烷）添加到过表达Opiorphins的质粒处理过的大鼠的饮用水中，可以预防priapic样疾病。在一个建立良好的阴茎勃起动物模型（伯克利镰状细胞小鼠，BERK小鼠）中，我们已经证明，在阴茎勃起样疾病发作之前，在体部组织中mSMR2（小鼠Opiorphin同源物）的表达升高。小鼠priapic-like病症的发病伴随着mSMR2的高水平表达和多胺代谢关键酶（精氨酸酶I、II和ODC）的上调。我们的证据表明，opiorphin和多胺合成途径的上调可能在与镰状细胞病相关的阴茎勃起障碍的发展中发挥作用，针对多胺合成途径的干预可能有助于预防镰状细胞病男性的阴茎勃起样病变。本研究的目的是验证一种假说，即镰状细胞病动物体内Opiorphin表达水平的升高可调节精氨酸分解代谢和多胺合成途径，从而在阴茎勃起症的发生中发挥作用。抑制Opiorphin表达或多胺合成途径可能是治疗阴茎勃起障碍的靶点。如果我们的研究证明了Opiorphins和多胺合成在镰状细胞病相关的阴茎勃起障碍发展中的作用，这不仅将确定新的药理靶点，而且还将确定哪些患者有发生阴茎勃起障碍的风险。

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.