腺苷介导的红细胞氧释放在阴茎勃起中的作用机制研究

Normal penile erection is a complex physiological process, which is not fully clarified at present. It is reported that physiological concentration of oxygen in corpus cavernosum modulates penile erection and decrease of oxygen level leads to depression of corpus cavernosum relaxation, which indicates that erythrocyte and oxygen release may play important role in the process of penile erection. Our previous study have demonstrated that adenosine signaling through A2B adenosine receptor contributed to induction of 2,3-diphosphoglycerate, an erythrocyte-specific metabolite that decreases the oxygen binding affinity of hemoglobin, to promote oxygen release from erythrocyte. In this research project, we will use different animal models to determine the role of erythrocyte and oxygen release in penile erection and address the underlying mechanism including: 1. How adenosine signaling pathway modulates oxygen release during the process of penile erection. 2. The role and downstream mechanism of adenosine signaling pathway mediated oxygen release in penile erection. 3. Whether the occurrence of erectile dysfunction is attributed to impaired oxygen release mediated by adenosine signaling pathway. In summary, this project may enhance the understanding of the mechanism of penile erection and provides novel therapeutic targets for erectile dysfunction in the future.

阴茎勃起是一个复杂的生理过程，其涉及的分子机制目前尚未完全明确。研究表明，阴茎海绵体内血氧浓度在勃起时迅速上升。降低氧气浓度能显著地抑制阴茎海绵体舒张，提示红细胞及其氧释放在阴茎勃起过程中发挥重要的作用。申请者前期的研究证实腺苷通过作用于外周血红细胞的A2B腺苷受体调节红细胞氧释放关键因子2，3-二磷酸甘油酸的活性，从而降低血红蛋白对氧的亲合力，促进红细胞释放氧气。前期的预实验发现腺苷能调控阴茎海绵体内红细胞的氧释放，从而介导阴茎勃起的生理过程，本项目拟围绕以下几方面展开研究：（1）阐明阴茎勃起过程中腺苷调控阴茎海绵体内红细胞氧气释放的分子机制；（2）探讨红细胞氧释放在阴茎勃起过程中的作用及分子机理；（3）构建勃起功能障碍动物模型，明确不同类型勃起功能障碍的发生是否与腺苷介导的红细胞氧释放障碍相关。本课题将加深对阴茎勃起分子机理的认识，为今后开辟勃起功能障碍新的药物治疗方法提供理论依据。

研究团队前期已证实腺苷信号通路在阴茎正常勃起和异常勃起中发挥着重要的作用。本课题研究了腺苷介导的红细胞氧释放在阴茎勃起中的作用，并深入探讨了其涉及的分子机制。研究发现，阴茎勃起过程中阴茎海绵体内血氧浓度和海绵体内压均显著升高，且呈正相关性。腺苷通过红细胞表面的A2B腺苷受体激活SphK1-S1P通路，从而调节2，3-二磷酸甘油酸水平，后者促进阴茎海绵体内红细胞释放氧气。氧气的释放通过激活PI3K/Akt/eNOS通路促进NO的合成，后者调节环鸟苷酸（cGMP）水平介导阴茎勃起。此外，本课题成功构建了糖尿病性阴茎勃起功能障碍的动物模型，研究发现勃起功能障碍动物模型中存在腺苷信号通路受损和红细胞氧气释放障碍，从而介导勃起功能障碍的发生。激活腺苷信号通路的活性，改善阴茎海绵体内的氧气释放，改善勃起功能，有望成为新的治疗靶点。