Adenosine Signaling, Priapism and Sickle Cell Disease

腺苷信号传导、阴茎异常勃起和镰状细胞病

• 批准号: 7636152
• 负责人: Yang Xia
• 金额: $ 34.67万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-05-01 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7636152
• 关键词: Adenosine; Adenosine A2B Receptor; Animal Model; Area; Biochemistry; Blood Vessels; Body of uterus; Cell surface; Coupled; Development; Disease; Erectile dysfunction; Etiology; Event; Fibrosis; Functional disorder; Human; In Vitro; Laboratories; Maintenance; Mediating; Molecular; Molecular Genetics; Mus; Muscle relaxation phase; Mutant Strains Mice; Mutation; Pathogenesis; Patients; Penile Erection; Physiological; Physiology; Play; Positioning Attribute; Priapism; Process; Production; Purinergic P1 Receptors; Receptor Signaling; Relaxation; Research; Research Activity; Role; Sickle Cell Anemia; Signal Pathway; Signal Transduction; Signaling Molecule; Smooth Muscle; Source; Therapeutic; Tissues; Transgenic Mice; adenosine deaminase; adenosine deaminase deficiency; base; cellular targeting; enzyme therapy; erection; experience; in vivo; insight; interest; male; novel; novel therapeutics; penis; public health relevance; receptor; response

DESCRIPTION (provided by applicant): Priapism is defined as prolonged penile erection occurring unassociated with sexual interest. 40% of male sickle cell disease (SCD) patients display priapism. The disorder is dangerous and urgent given its association with erectile tissue damage and erectile dysfunction. Current strategies to manage the disorder are poor due to lack of fundamental understanding of the pathophysiology of priapism. Recently my laboratory unexpectedly found that male adenosine deaminase (ADA)-deficient mice display features of priapism seen in humans, including spontaneous prolonged penile erection associated with increased vascular relaxation in response to neurostimulation with subsequent penile fibrosis. In addition, we demonstrated that reducing the accumulation of adenosine by ADA enzyme therapy relieved spontaneous prolonged penile erection and corpus cavernosal strip relaxation both in vivo and in vitro. Moreover, the analysis of four adenosine receptor deficient mice revealed that the A2B adenosine receptor (A2BR) is essential for adenosine-mediated penile relaxation and erection and that upregulated A2BR signaling contributes to priapic activity in ADA-deficient mice. Finally we found that priapic activity in the SCD transgenic mouse, a well accepted priapic animal model, is also due to elevated adenosine signaling via A2BR, suggesting a general contributory role of adenosine and A2BR signaling in priapism. Thus, in two independent lines of mutant mice, one with ADA deficiency and another with SCD, we have shown that excessive adenosine accumulation in the penis, coupled with increased A2BR signaling, contributes to priapism. We now propose to extend these observations by determining the cellular targets and signaling pathways associated with adenosine-induced priapism, the molecular mechanism of increased adenosine production in priapism and the general role of adenosine signaling in the initiation and maintenance of normal penile erection. The following specific aims are proposed. I. What are the intracellular targets and signaling pathways involved in adenosine-induced priapism? II. What are the molecular mechanisms generating excess adenosine in priapism? III. What are the sources of adenosine in the penis and what regulates its production during initiation and maintenance of normal penile erection? Specific Aims I and II represent a continuation of our efforts to understand the molecular basis of adenosine- induced priapism. Specific Aim III represents an expansion of these efforts to understand the role of adenosine signaling in normal penile erection. As a result of our ongoing research activities we have available all the necessary lines of mutant mice as well as relevant research experience in areas of biochemistry, molecular genetics and physiology needed to conduct the research proposed here. Proposed research is likely to reveal an important role for adenosine signaling in several aspects of the penile erection process and highlight various therapeutic opportunities to treat priapism and other erectile disorders. PUBLIC HEALTH RELEVANCE: Priapism is defined as abnormal prolonged penile erection occurring unassociated with sexual interest. About 40% sickle cell disease patients display priapism. The disorder is dangerous and urgent given its association with immediate erectile tissue damage and eventual erectile dysfunction. Current strategies to manage the disorder are poor due to lack of fundamental understanding of the pathophysiology of priapism. Our laboratory recently has observed priapism in a line of mutant mice with a specific genetic defect. These mutant mice display features of priapism seen in humans, including prolonged penile erection and evidence of penile tissue fibrosis. As a result of the genetic defect these mice overproduce adenosine, a signaling molecule that elicits many physiological effects by activating specific receptors on the surface of cells. Our recent findings suggest that overproduced adenosine is also responsible for priapism seen in sickle cell disease transgenic mice, a well accepted priapic animal model, suggesting the general contributory role of excess adenosine via activating its receptor in priapism. We propose to use these mutant mice as an animal model to investigate the role of adenosine signaling in priapism and normal penile erection in general. This research will provide us with novel insight into mechanisms of adenosine signaling in penile erection, priapism and eventually, erectile dysfunction. By understanding the molecular events involved in the development of priapism, we seek to develop novel therapeutic strategies to treat this disease.

描述（由申请人提供）：阴茎勃起被定义为与性兴趣无关的阴茎勃起时间延长。 40% 的男性镰状细胞病 (SCD) 患者表现出阴茎异常勃起。鉴于其与勃起组织损伤和勃起功能障碍的相关性，该疾病是危险且紧急的。由于缺乏对阴茎异常勃起病理生理学的基本了解，目前治疗该疾病的策略很差。最近，我的实验室出乎意料地发现，雄性腺苷脱氨酶（ADA）缺陷小鼠表现出人类中常见的阴茎异常勃起的特征，包括自发延长阴茎勃起，并与神经刺激引起的血管松弛增加相关，并随后导致阴茎纤维化。此外，我们还证明，通过 ADA 酶疗法减少腺苷的积累，可以在体内和体外缓解自发延长的阴茎勃起和海绵体条松弛。此外，对四只腺苷受体缺陷小鼠的分析表明，A2B 腺苷受体 (A2BR) 对于腺苷介导的阴茎松弛和勃起至关重要，并且上调的 A2BR 信号传导有助于 ADA 缺陷小鼠的阴茎勃起活动。最后，我们发现 SCD 转基因小鼠（一种广泛接受的阴茎勃起动物模型）中的阴茎勃起活动也是由于通过 A2BR 的腺苷信号传导升高所致，这表明腺苷和 A2BR 信号传导在阴茎勃起中具有普遍的贡献作用。因此，在两个独立的突变小鼠系中，一个具有 ADA 缺陷，另一个具有 SCD，我们发现阴茎中腺苷的过量积累，加上 A2BR 信号传导的增加，有助于阴茎勃起。我们现在建议通过确定与腺苷诱导的阴茎勃起相关的细胞靶标和信号通路、阴茎勃起中腺苷产生增加的分子机制以及腺苷信号在正常阴茎勃起的启动和维持中的一般作用来扩展这些观察。提出以下具体目标。一、腺苷诱导阴茎异常勃起的细胞内靶点和信号通路有哪些？二.阴茎异常勃起时产生过量腺苷的分子机制是什么？三．阴茎中腺苷的来源是什么？在正常阴茎勃起的起始和维持过程中，什么调节腺苷的产生？具体目标 I 和 II 代表我们继续努力了解腺苷诱导的阴茎异常勃起的分子基础。具体目标 III 代表了这些努力的扩展，以了解腺苷信号传导在正常阴茎勃起中的作用。由于我们正在进行的研究活动，我们已经获得了进行此处提出的研究所需的所有必要的突变小鼠品系以及生物化学、分子遗传学和生理学领域的相关研究经验。拟议的研究可能会揭示腺苷信号在阴茎勃起过程的几个方面的重要作用，并强调治疗阴茎异常勃起和其他勃起障碍的各种治疗机会。公共健康相关性：阴茎异常勃起被定义为与性兴趣无关的异常长时间阴茎勃起。大约40%的镰状细胞病患者表现出阴茎异常勃起。由于该疾病与直接勃起组织损伤和最终的勃起功能障碍有关，因此是危险且紧急的。由于缺乏对阴茎异常勃起病理生理学的基本了解，目前治疗该疾病的策略很差。我们的实验室最近在一系列具有特定遗传缺陷的突变小鼠中观察到阴茎异常勃起。这些突变小鼠表现出人类阴茎勃起的特征，包括阴茎勃起时间延长和阴茎组织纤维化的证据。由于遗传缺陷，这些小鼠过量产生腺苷，腺苷是一种信号分子，通过激活细胞表面的特定受体而引发许多生理效应。我们最近的研究结果表明，过量产生的腺苷也是镰状细胞病转基因小鼠（一种广为接受的阴茎勃起动物模型）中观察到的阴茎异常勃起的原因，这表明过量腺苷通过激活其受体在阴茎异常勃起中发挥一般贡献作用。我们建议使用这些突变小鼠作为动物模型来研究腺苷信号传导在阴茎异常勃起和正常阴茎勃起中的作用。这项研究将为我们提供关于阴茎勃起、阴茎异常勃起以及最终勃起功能障碍中腺苷信号传导机制的新见解。通过了解阴茎异常勃起发展所涉及的分子事件，我们寻求开发新的治疗策略来治疗这种疾病。