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

基本信息

批准号：
8242646
负责人：
Yang Xia
金额：
$ 31.85万
依托单位：
UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-05-01 至 2014-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8242646
关键词：
Adenosine Adenosine A2B Receptor Animal Model Area Biochemistry Blood Vessels 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 receptor response

项目摘要

PROJECT SUMMARY/ABSTRACT 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.

项目概要/摘要阴茎异常勃起被定义为与性兴趣无关的阴茎勃起时间延长。 40% 男性镰状细胞病（SCD）患者表现出阴茎异常勃起。鉴于其关联性，这种疾病是危险且紧急的伴有勃起组织损伤和勃起功能障碍。目前治疗这种疾病的策略很差，因为缺乏对阴茎异常勃起的病理生理学的基本了解。最近我的实验室意外地发现雄性腺苷脱氨酶（ADA）缺陷的小鼠表现出人类所见的阴茎异常勃起的特征，包括与血管松弛反应增加相关的自发性延长阴茎勃起神经刺激导致阴茎纤维化。此外，我们还证明了减少积累腺苷 ADA 酶疗法可缓解自发延长的阴茎勃起和海绵体体内和体外的条带松弛。此外，对四种腺苷受体缺陷小鼠的分析揭示 A2B 腺苷受体 (A2BR) 对于腺苷介导的阴茎松弛至关重要 ADA 缺陷小鼠的勃起和 A2BR 信号上调有助于阴茎勃起活动。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归因于通过 A2BR 的腺苷信号传导升高，表明腺苷和 A2BR 信号传导的一般贡献作用在阴茎勃起。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，我们研究表明，阴茎中腺苷积累过多，加上 A2BR 信号传导增加，有助于阴茎勃起。我们现在建议通过确定细胞目标和与腺苷诱导的阴茎异常勃起相关的信号通路，增加的分子机制阴茎异常勃起中腺苷的产生以及腺苷信号传导在启动和维持中的一般作用阴茎的正常勃起。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以及在起始过程中调节其产生的因素和维持正常的阴茎勃起？具体目标 I 和 II 代表我们继续努力了解腺苷的分子基础- 诱发阴茎异常勃起。具体目标 III 代表了这些努力的扩展，以了解正常阴茎勃起中的腺苷信号传导。由于我们正在进行的研究活动，我们可以获得所有必要的突变小鼠品系以及生物化学领域的相关研究经验，进行此处提出的研究需要分子遗传学和生理学。拟议的研究是可能揭示腺苷信号在阴茎勃起过程的几个方面的重要作用，强调治疗阴茎异常勃起和其他勃起障碍的各种治疗机会。

项目成果

期刊论文数量（7）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Purinergic control of red blood cell metabolism: novel strategies to improve red cell storage quality.

红细胞代谢的嘌呤能控制：提高红细胞储存质量的新策略。

DOI：
发表时间：
2017-10
期刊：
影响因子：
0
作者：
Sun, Kaiqi;D'alessandro, Angelo;Xia, Yang
通讯作者：
Xia, Yang

Beneficial and detrimental role of adenosine signaling in diseases and therapy.

腺苷信号传导在疾病和治疗中的有益和有害作用。

DOI：
10.1152/japplphysiol.00350.2015
发表时间：
2015-11-15
期刊：
Journal of applied physiology
影响因子：
3.3
作者：
Hong Liu;Yang Xia
通讯作者：
Yang Xia

Red blood cell β-adrenergic receptors contribute to diet-induced energy expenditure by increasing O2 supply.

红细胞β-肾上腺素能受体通过增加O2 供应来促进饮食引起的能量消耗。

DOI：
发表时间：
2017-07-20
期刊：
影响因子：
8
作者：
Kim, Eun Ran;Fan, Shengjie;Akhmedov, Dmitry;Sun, Kaiqi;Lim, Hoyong;O'Brien, William;Xu, Yuanzhong;Mangieri, Leandra R;Zhu, Yaming;Lee, Cheng;Chung, Yeonseok;Xia, Yang;Xu, Yong;Li, Feng;Sun, Kai;Berdeaux, Rebecca;Tong, Qingchun
通讯作者：
Tong, Qingchun

Metabolomic and molecular insights into sickle cell disease and innovative therapies.

对镰状细胞病和创新疗法的代谢组学和分子学见解。