杞菊地黄丸视网膜保护效应的系统药理学机制研究

Degeneration of retinal pigment epithelium and photoreceptor cell death are the central mechanisms underling the pathogenesis of a variety of retinal degenerative disorders, including age-related macular degeneration and retinitis pigmentosa, which remain as unresolved challenges clinically due to lack of effective therapies. Our previous studies have uncovered that complex crosstalking mechanisms are implicated in the pathogenesis of photoreceptor cell death and related retinopathies. QiJuDiHuang Formulation (QJDH) has a long history of clininal application as a base formation for the treatment of age-related macular degeneration and other retinal degenerative disorders. Although QJDH is recognized as therapeutically effective, the mechanisms underlining its retinal protective effects remain to be explored. Therefore, our current study propose to employ the systems pharmacology approach and compare the protective effects of QJDH and major formulations derived from QJDH, namely BuShen, YangGan and QinGan composition, on photoreceptor cells and RPE. Further mechanistic studies will be focused on elucidating the impact of each of herbal formulation on oxidative stress, inflammatory responses, G-protein coupled receptors and endoplasmic reticulum stress. In the end, we aim to delineate the cellular target and molecular element that mediate the synergistic effect of different component of QJDH, which will ultimately provide scientific and experimental evidence supporting the clinical application of QJDH in the treatment of retinal degenerative disorders.

视网膜色素上皮细胞（RPE）变性、光感受器细胞（photoreceptor)死亡是多种严重危害视力健康的视网膜退行性病变的共同病理环节，现代医学尚缺乏有效干预手段。申请人前期工作提示多重生物学机制相互关联，共同导致了RPE及photoreceptor的死亡变性。经典的杞菊地黄丸是中医临床广泛应用的治疗视网膜退行性病变的基础方剂，然而针对其RPE及photoreceptor的视网膜保护效应机制的认识尚存在大量空白。本项目将以RPE及photoreceptor为主要效应靶点，比较杞菊地黄丸及其滋补肾阴、补肾养肝、清肝拆方的视网膜保护作用，结合前期研究基础，从系统药理学的角度研究不同药物组方对氧化应激、炎症、G-蛋白偶联受体及其信号通路等相互关联的生化及分子信号通路的影响，深入探讨杞菊地黄丸全方不同治则指导下方药组合配伍协同干预的有效性及合理性，以期为杞菊地黄丸临床应用及优化提供新的生物学依据。

光感受器退行性改变是多种严重危害视力健康甚至致盲的视网膜疾病的核心病理基础，目前尚无有效干预手段。经典明目复方杞菊地黄丸长期应用于多种视网膜退行性病变的治疗，然而其是否具有光感受器保护作用尚待阐明。该项目基于光感受器退行性改变这一中心病理环节，在前期机制研究的基础上，采用小鼠光损伤模型，探讨并明确了杞菊地黄丸对光感受器细胞可能发挥的保护效应及机制。项目的研究结果首次揭示了杞菊地黄丸与Gs 偶联 GPCR 通路抑制剂美托洛尔协同保护光感受器细胞的效应。研究结果提示杞菊地黄丸与美托洛尔联合干预对视网膜结构及功能、视网膜二级神经元损伤及反应性胶质增生具有显著的干预作用。此外，结合拆方的研究结果，本研究提示光感受器细胞保护需杞菊地黄丸全方与Gs-GPCR通路的协同干预。因此，本研究结果为常用中药复方杞菊地黄丸临床“精准”应用于相关视网膜退行性疾病的治疗提供了科学的实验依据。