Involvement of opiorphins and polyamine synthesis in the development of priapism

阿片啡肽和多胺合成参与阴茎异常勃起的发展

• 批准号: 8041693
• 负责人: KELVIN P DAVIES
• 金额: $ 24.9万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-15 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8041693
• 关键词: Affect; Animal Model; Animals; Arginine; Biochemical; Biological Markers; Blood; Blood Circulation; Catabolism; Complex; Consultations; Development; Disease; Enzymes; Erectile dysfunction; Gene Expression; Genetic Transcription; Goals; Homologous Gene; Human; Incidence; Injection of therapeutic agent; Institutional Review Boards; Intervention; Label; Measures; Metabolism; Molecular; Mus; Muscle Tonus; Ornithine Decarboxylase; Ornithine Decarboxylase Inhibitor; Paper; Pathology; Pathway interactions; Patients; Pharmacological Treatment; Plasma; Plasmids; Play; Polyamine Catabolism; Polyamines; Priapism; Proteins; Rattus; Regulation; Reporting; Research; Risk; Role; Sickle Cell; Sickle Cell Anemia; Signal Pathway; Smooth Muscle; Stream; Testing; Tissues; United States National Institutes of Health; Up-Regulation; Work; arginase; drinking water; erection; inhibitor/antagonist; men; mouse model; novel; prevent; small hairpin RNA

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.

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世界数百万人的疾病，目前尚无药物治疗方法。阴茎异常勃起的发展机制很复杂，目前尚不清楚。我的小组最近发表的一篇论文描述了阴茎异常勃起的发展机制，该机制为开发新的治疗方法提供了潜力。退役种鼠体中编码 Opiorphins（大鼠中为 Vcsa1，人类中为 ProL1 和 hSMR3A/B）的基因过度表达将导致类似阴茎勃起的病症。我们最近报道，退休种鼠的体组织中Opiorphins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。当将 ODC 抑制剂（1,3-二氨基丙烷）添加到用过表达 Opiorphin 的质粒处理过的大鼠的饮用水中时，它可以预防阴茎勃起样病症。在一个完善的阴茎勃起动物模型（伯克利镰状细胞小鼠，BERK 小鼠）中，我们证明在阴茎勃起样病症发作之前，在身体组织中 mSMR2（小鼠 Opiorphin 同源物）的表达升高。小鼠中类似阴茎勃起症状的发作伴随着更高水平的 mSMR2 表达以及多胺代谢中关键酶（精氨酸酶 I 和 II 以及 ODC）的上调。我们的证据表明，Opiorphins 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措施可能有助于预防镰状细胞病男性的阴茎异常勃起样病变。该提案的目的是检验以下假设：患有镰状细胞病的动物体内 Opiorphin 表达水平的增加可调节精氨酸分解代谢和多胺合成途径，从而在阴茎异常勃起的发展中发挥作用。 Opiorphin 表达或多胺合成途径的抑制可能是治疗阴茎异常勃起的目标。如果我们的研究证明 Opiorphin 和多胺合成在与镰状细胞病相关的阴茎勃起的发展中发挥作用，那么这不仅可以确定新的药理学靶点，还可以确定哪些患者有发生阴茎勃起的风险的生物标志物。 公众健康相关性：阴茎异常勃起，即在没有性刺激的情况下长时间勃起，可能会导致身体组织不可逆转的损伤和勃起功能障碍。它与多种疾病有关，但在患有镰状细胞病的男性中尤其普遍，其发病率约为 40%。目前尚无足够的药物干预对其治疗。我们在此提出的工作将调查 Opiorphin 和多胺合成在阴茎勃起中的作用，有可能确定其治疗的新药理学靶点，并确定生物标志物来确定哪些患者有发生阴茎勃起的风险。