雄激素受体及共调节因子在雄激素调控勃起信号通路VIP/cAMP中的作用研究

Androgen plays important roles in the process of penile erection through complicated mechanisms. The applicant firstly discovered that the expression of erectile neurotransmitter-vasoactive intestinal polypeptide (VIP) mRNA kept unchanged in the medium of low-concentration of androgen, and then found that the effect of VIP on erection was more significantly in castrated rats than in normal rats. Therefore, it is deserved of further research on the changes of expression and efficacy of androgen receptor (AR) and its co-regulators in the condition of low-testosterone medium, resulting in augmenting effects of VIP/cAMP on penile erection... In the present study, a rat model with varied androgen-concentrations and activities of AR will be applied. By electric stimulation of cavernous nerve, and monitoring of intracavernosal pressure, and corpus cavernosum (CC) strip bath and penile artery ring tests, as well as inhibiting the expression of AR with shRNA in cavernosal smooth muscle cells (CSMC), specifically prohibiting activities of AR coregulator CBP/p300, we will further study the regulatory effects of androgen on AR and its coregulators, and the effects of AR and its coregulators on signal transduction VIP/cAMP pathway under the condition of different levels of androgen. By investigating the effects of AR signaling on VIP/cAMP pathway, we want to demonstrate the mechanisms by which androgen regulates the erectile signal transduction VIP/cAMP pathway via AR/coregulators, and to uncover the process of regulating action of androgen on penile erection.

雄激素对阴茎勃起发挥重要作用，其机理复杂。申请者首先发现勃起神经递质血管活性肠多肽（VIP）的VIPmRNA表达在低雄激素浓度时没有明显变化，后又发现VIP诱导勃起在去势大鼠更加明显。低雄激素浓度时雄激素受体（AR）及其共调节因子活性与表达可能改变，介导VIP/cAMP促进勃起的过程及机理有待证实。..本课题拟建立雄激素浓度及AR活性变化的大鼠模型。应用电刺激海绵体神经、海绵体测压、平滑肌肌条和微血管环等实验；采用RNAi抑制海绵体平滑肌细胞AR的表达，特异性抑制AR共调节因子CBP/p300活性等方法，研究雄激素对AR及共调节因子表达和活性的影响，以及AR和共调节因子在不同雄激素浓度下对勃起信号通路VIP/cAMP的作用，为全面揭示雄激素调控阴茎勃起过程奠定基础。

雄激素对阴茎勃起发挥重要作用，机理复杂。然而，低雄激素浓度时雄激素受体（AR）及其共调节因子表达和活性的改变，以及介导血管活性肠多肽（VIP）/cAMP促进勃起的过程及机理有待证实。本课题通过建立雄激素浓度及AR 活性变化的大鼠模型，应用电刺激海绵体神经、海绵体测压、平滑肌肌条和微血管环等实验，探讨（1）雄激素浓度和AR活性变化对VIP调控勃起作用的影响。（2）探讨雄激素浓度变化对AR及共调节因子表达的影响，AR及共调节因子信号通路与VIP/cAMP/PKA 信号通路的相互作用，进而明确低雄激素浓度时勃起功能维持的机制。本课题研究发现（1）VIP发挥作用可能并不依赖雄激素浓度或AR活性，属于雄激素非依赖性的勃起神经递质。VIP/AC/cAMP信号通路可能在正常雄激素浓度时起辅助作用、而在低雄激素浓度时起重要作用。（2）雄激素对AR及其共调节因子有复杂的调控作用，AR及共调节因子信号通路与VIP/cAMP/PKA 信号通路之间存在交叉激活机制。低雄激素时，阴茎海绵体平滑肌细胞内AR表达不变或降低，而AR共激活因子（CBP、p300、SRC-1）表达增高。在AR共激活因子的协同作用下，AR及共调节因子信号通路通过交叉激活而增强VIP/cAMP/PKA信号通路的作用，从而使得低雄激素浓度时勃起功能得以维持。本研究结果有利于揭示低雄激素水平下阴茎勃起功能维持的机理，完善雄激素调控阴茎勃起的理论，为ED的治疗开辟新的途径。