腺苷信号通路在糖尿病性勃起功能障碍中的作用及机制研究

Diabetes is a very important risk factor of erectile dysfunction (ED), it is reported that more than 50% of diabetes patients display ED, which seriously affects the quality of life of them. Currently, very little is known about the underlying mechanism of diabetes induced ED. Our previous study has demonstrated that adenosine production plays essential role in the physiological process of normal penile erection via A2B adenosine receptor. Additionally, we found that the adenosine production during penile erection and A2B adenosine receptor expression level in diabetes induced ED rat model were significantly reduced compared to control rat, which indicated the impairment of adenosine signaling may play some pathological role in diabetes induced ED. In this research project, we will use diabetes induced ED rat as animal model to further determine the role of impaired adenosine signaling in diabetes induced ED and address the underlying mechanism based on the following hypothesis: 1. Down-regulating cAMP-PKA to induce ED; 2. Inhibiting the activation of PI3K/Akt/eNOS signaling pathway and decreasing the NO production during penile erection, which finally leads to reduction of cGMP level; 3. Regulating the activity of PDE5. Moreover, we plan to explore the potential therapeutic strategies for diabetes induced ED by targeting adenosine signaling pathway. In summary, this research project may enhance the understanding of the mechanism of diabetes induced ED and provide therapeutic targets for diabetes induced ED for the future study.

糖尿病是阴茎勃起功能障碍（ED）的重要危险因素，超过50%的糖尿病患者存在ED，严重影响患者的生活质量。目前，糖尿病性ED的发病机理尚未完全阐明。申请者前期的研究发现阴茎勃起过程中腺苷的生成通过A2B腺苷受体在阴茎勃起中发挥着重要作用，糖尿病性ED大鼠阴茎勃起过程中阴茎内腺苷的生成和A2B腺苷受体水平较正常大鼠显著降低，提示腺苷信号通路的受损可能与糖尿病性ED的发生相关。本项目拟利用糖尿病性ED大鼠模型，明确腺苷信号通路在糖尿病性ED发生的作用，同时从以下几方面探讨其机制：(1)影响cAMP-PKA通路水平；(2)影响PI3K/Akt/eNOS通路水平和NO的生成，从而影响NO-cGMP通路活性；(3)影响PDE5的活性。此外，探索上调腺苷信号通路活性以治疗糖尿病性ED的可行性，为今后的临床应用提供理论依据，有望开辟新的药物治疗手段。

糖尿病是阴茎勃起功能障碍（ED）的重要危险因素，超过50%的糖尿病患者存在ED，严重影响患者的生活质量。目前，糖尿病性ED 的发病机理尚未完全阐明。项目负责人前期的研究发现阴茎勃起过程中腺苷的生成通过A2B 腺苷受体在阴茎勃起中发挥着重要作用，阴茎组织中腺苷浓度增高可通过A2B 腺苷受体导致小鼠的阴茎异常勃起。本课题研究成功地构建了糖尿病性ED 大鼠模型，研究发现糖尿病性ED 大鼠阴茎勃起过程中阴茎内腺苷的生成和A2B 腺苷受体的表达水平较正常大鼠均显著降低。通过A2B腺苷受体激动剂Bay60-6583的治疗，糖尿病性ED大鼠阴茎勃起功能障碍得到明显改善，说明糖尿病性ED 的发生与A2B腺苷信号通路的受损密切相关。进一步研究证实，A2B腺苷信号通路受损通过以下两方面分子机制导致糖尿病性ED的发生：（1）影响cAMP-PKA 通路的水平；（2）影响PI3K/Akt/eNOS 通路的激活和NO 的生成。此外，本课题亦证实A2B腺苷受体激动剂Bay60-6583能安全有效地改善糖尿病性ED大鼠的阴茎勃起功能，为今后的临床药物试验提供理论依据，有望开辟新的药物治疗手段。