Involvement of opiorphins and polyamine synthesis in the development of priapism

描述（由申请人提供）：阴茎异常勃起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。阴茎异常勃起的发病机制是复杂的，而且还不清楚。我的小组最近的一篇论文描述了阴茎异常勃起的发展机制，这为开发新的药物治疗方法提供了可能。退休饲养大鼠体内编码阿片肽（大鼠中的Vcsa 1和人类中的ProL 1和hSMR 3 A/B）的基因的过表达将导致阴茎异常勃起样病症。我们最近报道，在退休的饲养大鼠的身体组织中的过量表达的阿片肽的结果在上调精氨酸catalysts通过激活鸟氨酸脱羧酶（ODC）和多胺的合成。一种ODC抑制剂（1，3-二氨基丙烷），当添加到用过表达Opiorphins的质粒处理的大鼠的饮用水中时，它可以预防阴茎异常勃起样病症。在阴茎异常勃起的良好建立的动物模型（伯克利镰状细胞小鼠，BERK小鼠）中，我们已经证明在阴茎异常勃起样病症发作之前，在身体组织中存在mSMR 2（小鼠阿片肽同源物）的表达升高。小鼠中阴茎异常勃起样病症的发作伴随着较高水平的mSMR 2表达和多胺代谢中关键酶（脱氢酶I和II以及ODC）的上调。我们的证据表明，阿片肽和多胺合成途径的上调可能在与镰状细胞病相关的阴茎异常勃起的发展中发挥作用，针对多胺合成途径的干预可能有助于预防男性镰状细胞病患者的阴茎异常勃起样病变。本提案的目的是检验镰状细胞病动物体内阿片肽表达水平增加调节精氨酸catenin和多胺合成途径，从而在阴茎异常勃起的发展中发挥作用的假设。抑制阿片肽表达或多胺合成途径可能代表治疗阴茎异常勃起的靶点。如果我们的研究证明了阿片肽和多胺合成在与镰状细胞病相关的阴茎异常勃起的发展中的作用，这不仅将确定新的药理学靶点，而且还将确定哪些患者有发生阴茎异常勃起的风险。 公共卫生相关性：阴茎异常勃起是一种在没有性刺激的情况下长时间勃起，可能导致身体组织不可逆的损伤和勃起功能障碍。它与几种疾病有关，但在镰状细胞病男性中特别普遍，其发病率约为40%。目前，没有足够的药物干预治疗。我们在这里提出的工作将研究阿片肽和多胺合成在阴茎异常勃起中的作用，可能确定其治疗的新药理学靶点，以及确定用于确定哪些患者有发生阴茎异常勃起风险的生物标志物。

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.