The (patho)physiological role(s) of CYP450-mediated mechanism(s) in the ophthalmic artery

CYP450介导机制在眼动脉中的（病理）生理作用

• 批准号: 397969102
• 负责人: Dr. Caroline Manicam
• 金额: --
• 依托单位: Augenklinik und Poliklinik
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2018
• 资助国家: 德国
• 起止时间: 2017-12-31 至 2022-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/397969102?language=en
• 关键词: patho; physiological; role; CYP450; mediated

While the vascular-related risk factor is not a new concept in the pathogenesis of glaucoma, alterations in cell signalling mechanisms and proteome changes underlying perturbed retrobulbar microcirculation, particularly the ophthalmic artery, are still unknown. Our preliminary studies have demonstrated that the cytochrome P450 (CYP450) pathway plays a key role in mediating ophthalmic arterial vasodilatory responses. Therefore, the main aim of this study is to investigate the (patho)physiological roles of the CYP450-mediated signalling or its lack thereof, in the ophthalmic microcirculation by addressing three major hypotheses. To date, the identity, expression and mechanisms of CYP450-derived eicosanoids and potential role of the main metabolizing enzyme of lipid mediators, soluble epoxide hydrolase (sEH), in the regulation of ophthalmic vascular tone and remodelling are uncharacterized. Hence, the first hypothesis is sEH inhibition would confer vasoprotection when exposed to glaucoma-related risk factors and insults by enhancing the bioavailability of CYP450-derived eicosanoids in the ophthalmic artery. This investigation will determine how the CYP450/sEH signalling maintains ophthalmic arterial integrity and what specific pathway(s) and/or mediator(s) are involved. We also demonstrated that this vascular bed possesses inherent compensatory mechanisms that preserve vasodilation when a signalling pathway is impaired. Thus, the second hypothesis to be tested is the ophthalmic artery is able to compensate and retain near-normal vascular responses in chronic lack of CYP450. This investigation will elucidate the underlying proteome, cellular and vascular structural adaptation processes that strive to buffer potential detrimental effects due to the lack of CYP450-mediated signal transduction. The third hypothesis is dietary supplementation with omega-3 fatty acids (ω3-PUFAs) would act as alternative substrates and prevent vascular dysfunction attributed to the chronic lack of CYP450. The findings of this investigation are envisioned to unravel potential shift(s) in the compensatory molecular profiles attributed to PUFAs in the ophthalmic artery. On the other hand, we have also demonstrated that gap junctions work in concert with CYP450 and the Kv1.6 channel is found for the first time to be involved in mediating vasodilatory responses. However, there is still a huge gap in knowledge about the complementary mechanisms involving gap junctional connexins and Kv1.6 channel in this artery. Thus, the final investigation will elucidate the intercellular communication networks of both components and potential alterations in their interactome when CYP450/sEH is lacking. In gist, this study will characterize the (patho)physiological role(s) of CYP450-mediated mechanism(s) in the ophthalmic artery that will facilitate future translational efforts in improving ocular perfusion in glaucoma.

虽然血管相关危险因素在青光眼发病机制中并不是一个新概念，但眼球后微循环（尤其是眼动脉）受到干扰的细胞信号传导机制的改变和蛋白质组的变化仍然未知。我们的初步研究表明，细胞色素 P450 (CYP450) 通路在介导眼动脉血管舒张反应中发挥着关键作用。因此，本研究的主要目的是通过解决三个主要假设来研究 CYP450 介导的信号传导或其缺乏在眼部微循环中的（病理）生理作用。迄今为止，CYP450 衍生的类二十烷酸的身份、表达和机制以及脂质介质的主要代谢酶可溶性环氧化物水解酶 (sEH) 在调节眼部血管张力和重塑中的潜在作用尚不清楚。因此，第一个假设是，当暴露于青光眼相关危险因素和损伤时，sEH 抑制可通过增强眼动脉中 CYP450 衍生的类二十烷酸的生物利用度来提供血管保护。这项研究将确定 CYP450/sEH 信号传导如何维持眼动脉完整性以及涉及哪些特定途径和/或介质。我们还证明，这种血管床具有固有的代偿机制，可以在信号通路受损时保持血管舒张。因此，要测试的第二个假设是眼动脉能够在长期缺乏 CYP450 的情况下补偿并保持接近正常的血管反应。这项研究将阐明潜在的蛋白质组、细胞和血管结构适应过程，努力缓冲由于缺乏 CYP450 介导的信号转导而产生的潜在有害影响。第三个假设是膳食补充 omega-3 脂肪酸 (ω3-PUFA) 可作为替代底物并预防因长期缺乏 CYP450 导致的血管功能障碍。这项研究的结果有望揭示眼动脉中多不饱和脂肪酸引起的代偿性分子谱的潜在变化。另一方面，我们还证明间隙连接与 CYP450 协同作用，并且首次发现 Kv1.6 通道参与介导血管舒张反应。然而，对于该动脉中涉及间隙连接蛋白和 Kv1.6 通道的互补机制的了解仍然存在巨大差距。因此，最终的研究将阐明两个组件的细胞间通讯网络以及当 CYP450/sEH 缺乏时它们的相互作用组的潜在变化。简而言之，本研究将描述 CYP450 介导机制在眼动脉中的（病理）生理作用，这将有助于未来改善青光眼眼灌注的转化工作。