难治性勃起功能障碍的关键机制：腺苷A2B受体介导的AMPK-自噬信号通路异常

难治性勃起功能障碍（ED）是指单独应用磷酸二酯酶5抑制剂治疗无效的ED，常见于糖尿病、盆底损伤及老年患者。我们用基因敲除小鼠证实，腺苷A2B受体是阴茎勃起功能的关键靶点。我们进一步在糖尿病、神经损伤和老年三种ED大鼠模型中发现腺苷A2B受体表达均降低，而给予腺苷A2B受体激动剂后勃起功能则明显改善。已有研究表明，腺苷A2B受体可激活腺苷酸活化蛋白激酶（AMPK），且激活AMPK有助于平滑肌细胞的自噬。我们推测：腺苷A2B受体可能介导了AMPK-自噬信号通路，进而改善勃起功能。为验证此假设，本项目将围绕“AMPK在三种难治性ED大鼠阴茎中的表达水平”，“AMPK活化水平对阴茎平滑肌自噬的影响”，“AMPK调节阴茎平滑肌自噬是否依赖于腺苷A2B受体”等问题开展一系列研究。力争阐明腺苷A2B受体介导的AMPK-自噬信号通路是难治性ED的共同机制，为其治疗提供新的思路。

Refractory erectile dysfunction (ED) refers to patients who have no response to the treatment of phosphodiesterase type 5 inhibitors, mainly in diabetes mellitus, pelvic floor injury and elderly patients. By using gene knockout mice, we have recently confirmed that the adenosine A2B receptor is a critical target of the erectile function. Furthermore, we found that the expression of adenosine A2B receptor was decreased in three ED models: diabetes, bilateral cavernous nerve injury and the aged; and that erectile function was significantly improved after treatment with adenosine A2B receptor agonist in the three models. Previous studies have shown that the adenosine A2B receptor can mediate the activation of AMP activated protein kinase (AMPK), and that the activated AMPK is involved in autophagy. Therefore, we hypothesize that the adenosine A2B receptor may mediate the AMPK-autophagy signaling pathway and modulate erectile function. To verify this hypothesis, the following specific aims are proposed: (1) The expression level of AMPK in the three rat models; (2) the effect of AMPK activation level on autophagy of penile smooth muscle cells; (3) whether the modulation of AMPK-autophagy in penile smooth muscle cells depends on adenosine A2B receptor. The answers to the above aims will provide us with novel insight into the molecular mechanism of refractory ED, which may provide new treatment ideas for ED patients.