PKC/PDE3A信号通路调控糖蛋白GPIbα介导的血小板凋亡的分子机制研究

生理或病理性因素可导致血小板膜糖蛋白Glycoprotein Ibα（GPIbα）依赖的血小板凋亡，引起血小板数量减少，进而造成出血性疾病的发生。申请人已发现并报道，蛋白激酶A（Protein kinase A, PKA）活性降低可导致血小板凋亡。预实验结果显示，GPIbα介导的血小板凋亡伴随PKA活性降低及蛋白激酶C/磷酸二酯酶3A（PKC/PDE3A）信号通路的活化；而抑制PKC/PDE3A可显著提高PKA活性，阻止GPIbα介导的血小板凋亡。因此，我们认为：PKC/PDE3A信号通路通过调控PKA活性参与GPIbα介导的血小板凋亡过程。本研究拟在预实验基础上，利用Western blot、洗涤血小板、基因敲除鼠等技术手段从分子、细胞、动物等三个层面探明PKC/PDE3A信号通路在GPIbα介导的血小板凋亡中的作用及其分子机制，为血小板减少性相关疾病的预防及治疗等方面提供理论依据。

Platelets membrane glycoprotein GPIbα (GPIbα)-dependent platelets apoptosis can be triggered by pathological and physiological stimuli leading to platelets dropping as well as the occurrence of hemorrhagic diseases. Our previous findings reported that protein kinase A (PKA) inhibition induced platelets apoptosis. Preliminary experiments showed that GPIbα-mediated apoptotic platelets had reduced PKA activity as well as activaiton of PKC/PDE3A signaling pathway. Moreover, inhibtion of PKC/PDE3A significantly elevated PKA activity, inhibited GPIbα-mediated platelets apoptosis. Thus, we hypothesized that PKC/PDE3A signaling was involved in GPIbα-mediated platelets apoptosis by mediating PKA activity. Based on the above data, the strategies of Western blot, washed platelets and gene konckout mice were used to explore the role and related molecular meachnisms of PKC/PDE3A in GPIbα-mediated platelets apoptosis. The expected findings will enrich the theoretic basis of prevention and treatment for platelet dropping-related diseases.