Involvement of opiorphins and polyamine synthesis in the development of priapism

描述(申请人提供)：异常勃起是一种影响美国数千名男性和全球数百万人的疾病，目前还没有药物治疗。异常勃起发生的机制很复杂，也不是很清楚。我的团队最近的一篇论文描述了异常勃起的发展机制，这为开发治疗异常勃起的新药理学方法提供了可能性。在退休繁育大鼠的语体中，Opiogins编码基因(大鼠的Vcsa1和人类的ProL1和hSMR3A/B)的过度表达将导致异常。我们最近报道了退役种鼠体内组织中奥匹林的过度表达通过激活鸟氨酸脱羧酶(ODC)和多胺合成而导致精氨酸分解代谢的上调。一种ODC抑制剂(1，3-二氨基丙烷)，当加入到过量表达奥匹奥芬的大鼠的饮用水中时，可以防止勃起的情况。在一个成熟的异常勃起动物模型(伯克利镰状细胞小鼠，Berk小鼠)中，我们已经证明在异常勃起之前，躯体组织中有mSMR2(小鼠阿片吗啡同系物)的高表达。伴随着mSMR2高水平的表达和多胺代谢中的关键酶(精氨酸酶I、II和ODC)的上调，小鼠的勃起类状态开始出现。我们的证据表明，鸦片吗啡和多胺合成途径的上调可能在与镰状细胞疾病相关的异常勃起的发生中发挥作用，针对多胺合成途径的干预可能有助于预防镰状细胞疾病男性的异常勃起样病理。这项建议的目的是验证一种假说，即在患有镰状细胞病的动物的语体中，阿片吗啡表达水平的增加调节精氨酸分解代谢和多胺合成途径，从而在异常勃起的发展中发挥作用。抑制阿片吗啡的表达或多胺合成途径可能是治疗异常勃起的靶点。如果我们的研究证明奥匹林和多胺合成在与镰状细胞疾病相关的异常勃起的发展中起作用，这不仅将识别新的药理靶点，而且还将确定哪些患者有发生异常勃起的风险的生物标志物。

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.