Androgen Regulation of Priapism in Sickle Cell Disease

描述（由申请人提供）：阴茎勃起症是一种非故意的，阴茎过度勃起复发的疾病，影响多种人群。它特别影响患有镰状细胞病（SCD）的男性，其中多达40%的人通常在年轻时患上这种疾病。这种疾病导致阴茎组织损伤和正常勃起能力的丧失，以及毁灭性的心理后果，因此不应轻视。今天，治疗方法仍然缺乏，许多男性和男孩忍受延迟和无效的治疗或与主要副作用相关的阴茎松弛的操作。最近为更好地理解这种疾病的科学所做的努力，为设计出合理有效的循证疗法带来了希望。现在了解到，与SCD相关的复发性缺血性阴茎勃起涉及与一氧化氮信号通路相关的正常阴茎勃起分子机制的畸变。雄激素在这一途径中发挥着直接的调节作用，雄激素缺乏经常发生在SCD中。因此，雄激素环境有助于阴茎勃起的病理生理是理所当然的。该建议的中心假设是雄激素水平和作用的下降导致与阴茎勃起相关的分子紊乱，相反，优化雄激素状态促进防止阴茎勃起的调节分子机制。该提案指定了一个转化项目，并结合临床前研究来验证这一假设（具体目标1），利用SCD小鼠模型研究下丘脑-垂体-性腺轴缺陷（具体目标2），以及研究精确睾酮替代对改善性腺功能低下的SCD男性勃起功能障碍和改善心理健康（具体目标3）的潜在益处的临床试验。该提案符合资助机构有关生殖生物学和睾丸功能的目标。

DESCRIPTION (provided by applicant): Priapism is a disorder of non-willful, excessive penile erection recurrences affecting diverse populations. It particularly affects males with sickle cell disease (SCD), and as many as 40% of these individuals develop the disorder often in their young adult years. The disorder accounts for penile tissue damage and loss of normal erectile ability in time, along with devastating psychological consequences, and thus it should not be trivialized. Today, treatments remain lacking, and many men and boys endure delayed and ineffective therapies or manipulations of penile flaccidity associated with major side-effects. Recent efforts to better understand the science of the disorder offer hope to devise evidence-based therapies that are rational and effective. It is now understood that recurrent, ischemic priapism associated with SCD involves aberrations of the molecular mechanisms of normal penile erection associated with the premier nitric oxide signaling pathway. Androgens are well described to exert a direct regulatory influence on this pathway, and androgen deficiency is frequently observed to occur in SCD. Accordingly, it stands to reason that the androgen milieu contributes to the pathophysiology of priapism. The central hypothesis of this proposal is that a decline in androgen levels and actions contributes to the molecular derangements associated with priapism and, conversely, optimizing androgen status promotes regulatory molecular mechanisms that protect against priapism. The proposal specifies a translational project and combines preclinical studies testing the hypothesis (Specific Aim 1) and investigating the hypothalamic-pituitary-gonadal axis defect (Specific Aim 2) using a mouse model of SCD and clinical trial investigating the potential benefit of precise testosterone replacement for ameliorating priapism and improving psychological well- being (Specific Aim 3) in hypogonadal men with SCD. The proposal fits with goals of the funding agency pertaining to reproductive biology and testis function.