Androgen Regulation of Priapism in Sickle Cell Disease

镰状细胞病中雄激素对阴茎异常勃起的调节

基本信息

批准号：
8875670
负责人：
Arthur Louis Burnett
金额：
$ 35.24万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-09-01 至 2017-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8875670
关键词：
Accounting Adverse effects Affect Androgens Attenuated Biochemical Biological Biology Blood Vessels Body Weight Clinical Clinical Trials Clinical assessments Defect Disease Environment Equipment and supply inventories Erectile dysfunction Evaluation Exhibits Fibrosis Flaccid Muscle Tone Frequencies Functional disorder Funding Agency Goals Histologic Histology Homeostasis Hormones Human Chorionic Gonadotropin Hypothalamic structure Immunohistochemistry In Vitro Individual Investigation Lead Link Measurement Mediator of activation protein Molecular Molecular Abnormality Monitor Mus Necrosis Nitric Oxide Nitric Oxide Pathway Nitric Oxide Signaling Pathway Nitrogen Organ Oxidation-Reduction Oxidative Stress Oxygen Pathogenesis Pathway interactions Patients Penile Erection Personal Satisfaction Phenotype Physiological Physiology Pilot Projects Pituitary Gland Plasma Population Heterogeneity Prevention Priapism Production Protocols documentation Quality of life Questionnaires Recurrence Regulation Reporting Reproductive Biology Research Science Seminal Vesicles Serum Sexual Health Sickle Cell Anemia Signal Transduction Specific qualifier value Steroid biosynthesis Testicular Tissue Testing Testis Testosterone Time Tissues Transgenic Organisms Well in self Work base boys design erection evidence base hypothalamic pituitary gonadal axis improved in vivo instrument leydig interstitial cell male men mouse model penis pre-clinical preclinical study psychologic psychological distress testosterone replacement therapy translational approach young adult

项目摘要

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.

描述（由申请人提供）：priapism是一种不愿意的，过度的阴茎勃起复发的疾病，影响了不同的人群。它特别影响镰状细胞疾病（SCD）的男性，其中多达40％的人经常在成年时期发展这种疾病。该疾病是阴茎组织的损害和时间上正常勃起能力的丧失，以及毁灭性的心理后果，因此不应被琐碎。如今，仍然缺乏治疗，许多男人和男孩忍受了与主要副作用相关的阴茎差的延迟和无效的疗法或操纵。更好地理解这种疾病科学的最新努力为制定理性和有效的循证疗法提供了希望。现在可以理解，与SCD相关的经常性缺血性培养主是涉及与高端一氧化氮信号通路相关的正常阴茎勃起的分子机制的畸变。很好地描述了雄激素，可以对该途径产生直接的调节作用，并且经常观察到雄激素缺乏症发生在SCD中。因此，它有理由认为雄激素环境有助于priapism的病理生理。该提议的核心假设是，雄激素水平和作用的下降有助于与priapism相关的分子扰动，相反，优化雄激素状态会促进保护抗priapism的调节分子机制。该提案指定了一个翻译项目，并结合了临床前研究测试假设（特定目的1），并使用SCD的鼠标模型和临床试验调查下丘脑 - 静态 - 垂体 - 轴轴缺陷（特定目标2），研究了对精确睾丸激素替代的潜在益处，以改善Priapism and priapism and Specting Psychal Orical Aim（特定的心理学）。该提案符合与生殖生物学和睾丸功能有关的资助机构的目标。