PDGF-C和PDGF-D：眼新生血管性疾病防治的新靶点及其机制研究

Ocular angiogenesis is the major reason of vision loss in numerous severe blinding diseases. Currently, VEGF is the only target gene that has been validated clinically for the treatment of ocular neovascular diseases. However, although the available antiangiogenic drugs against VEGF have shown clinical efficacy, they cannot treat all the patients with ocular neovascular diseases, and many challenging issues remain. Therefore, studies on new target genes important in ocular neovascular diseases are highly warranted. We have shown that PDGF-C and PDGF-D are two new potent angiogenic factors in different animal models, and their expression increases in a laser-induced choroidal neovascularization mouse model. Importantly, we found that the PDGF-C/D-mediated angiogenic effects are largely VEGF-independent, indicating that PDGF-C/D may be new important target genes in ocular neovascular diseases. Based on our previous work, we hypothesize that “PDGF-C/D may serve as new target genes for the treatment of ocular neovascular diseases”. In this study, we plan to use samples from patients with ocular neovascular diseases together with in vitro and in vivo models to investigate the expression of PDGF-C/D in ocular neovascular diseases; the possibility of inhibiting PDGF-C/D to treat such diseases, and the cellular and molecular mechanisms involved. The outcome of this study will not only provide new insight into the mechanisms of pathogenesis of ocular neovascular diseases, but may also lead to new therapeutic opportunities for their treatment.

眼新生血管形成是许多难治性致盲性眼病失明的主要原因和共同病理过程。 血管内皮生长因子(VEGF)是目前有效治疗眼新生血管性疾病的靶基因，但抗VEGF药物只对部分病人有效并易产生耐药。因此迫切需要研究眼新生血管形成的新机制和新靶基因。我们率先发现血小板源性生长因子新成员(PDGF)-C和PDGF-D是除VEGF之外的强促血管生长的因子，并在激光诱导脉络膜新生血管(CNV)动物模型中表达升高，提示PDGF-C/D促血管生成可能是眼新生血管形成的新机制和防治眼新生血管性疾病的新靶点。在前期基础上，本项目拟结合体内外实验模型和临床样本进一步研究：1.PDGF-C/D的表达与眼新生血管性疾病的关系；2.PDGF-C/D作为新靶点治疗眼新生血管性疾病的可能性及机制；3.PDGF-C/D作用的细胞和分子机制。研究结果将有助于揭示眼新生血管性疾病的发病新机制，并为研发眼新生血管性疾病的新药奠定基础。

眼新生血管形成是许多难治性致盲性眼病失明的主要原因和共同病理过程。血管内皮生长因子(VEGF)是目前有效治疗眼新生血管性疾病的靶基因，但抗VEGF药物只对部分病人有效并易产生耐药。因此迫切需要研究眼新生血管形成的新机制和新靶基因。我们率先发现血小板源性生长因子新成员PDGF-C和PDGF-D是除VEGF之外的强促血管生长的因子，并在激光诱导脉络膜新生血管(CNV)动物模型中表达升高，提示PDGF-C/D促血管生成可能是眼新生血管形成的新机制和防治眼新生血管性疾病的新靶点。基于项目负责人团队这些既有的研究基础，本项目结合体内外实验模型和临床样本进行了进一步研究，并将研究内容拓展到PDGF-C关键相关分子Caveolin-1及VEGF-B上。这些研究产生了5项代表性研究成果：(1)明确了PDGF-C的表达和眼新生血管性疾病的相关性；(2)发现了PDGF-CC的血管保护作用且可有效缓解视网膜色素变性动物模型中的血管退行性改变；(3)阐明了PDGF-C在眼新生血管性疾病中发挥作用的分子和细胞机制；(4)探索了PDGF-C关键相关基因和因子，有望和PDGF-C共同成为未来的药物靶点；（5）对PDGF-C作用，机制，以及临床应用潜能进行了系统的总结和梳理，发表了多篇相关综述，为进一步深入研究PDGF-C奠定了理论基础。