PDGF and Proliferative Vitreoretinopathy

描述(由申请人提供)：我们在上一次资助期间的发现包括，血小板衍生生长因子受体(PDGFRs)存在于人类增生性玻璃体视网膜病变(PVR)供者的视网膜前膜中，并且PDGFRs在该疾病的兔模型中是发生PVR所必需的。我们将继续研究PDGF在PVR中的作用，具体目标如下： 1.探讨阿尔法PDGFR比βPDGFR更易引起PVR的原因。在兔PVR模型中，表达αPDGFR的细胞比表达βPDGFR的细胞更有效地诱导PVR。我们将利用α和βPDGFR的嵌合体来确定使βPDGFR能够诱发PVR的αPDGFR区域(S)。 2.验证TGFβ通过PDGF-CC激活αPDGFR的假设。激活PDGFR是一种 这是兔PVR的先决条件，为此，我们将测试我们最近发现的依赖转化生长因子β(TGFbeta)的非常规激活αPDGFR的途径是否依赖于PDGF-CC。 3.确定增强视网膜色素上皮细胞(RPEs)PVR潜能的因素。在我们的兔模型中，成纤维细胞可以有效地诱导PVR，而RPE细胞则不能。这一缺陷将被用来确定提高RPE细胞PVR潜力的因素。 4.在动物模型中筛选人PVR供体视网膜前膜中促进PVR的因子的表达。我们将从人PVR供体的视网膜前膜中筛选在兔模型中对PVR至关重要的因子(如αPDGFR、激活的αPDGFR和该受体的配体)的表达。 这些研究将共同确定促进PVR的因素，并阐明这些因素之间的关系。此外，我们的发现将对兔子模型与人类疾病的相关性进行批判性评估。这些信息将指导未来开发预防和/或治疗人类PVR的方法。

DESCRIPTION (provided by applicant): Our findings in the previous grant period included that platelet-derived growth factor (PDGF) receptors (PDGFRs) are present in epiretinal membranes of human proliferative vitreoretinopathy (PVR) donors, and that PDGFRs are required for development of PVR in a rabbit model of the disease. We will continue to investigate the role of PDGF in PVR as outlined in these specific aims: 1. To investigate why the alphaPDGFR is better at causing PVR than the betaPDGFR. In the rabbit model of PVR, cells expressing the alphaPDGFR induce PVR much more effectively than do the same cells expressing the betaPDGFR. We will identify the region(s) of the alphaPDGFR that enable the betaPDGFR to induce PVR by using chimeras of the alpha and betaPDGFRs. 2. Test the hypothesis that TGFbeta activates the alphaPDGFR via PDGF-CC. Activation of the PDGFR is a prerequisite for PVR in rabbits, and in this aim we will test whether our recently discovered unconventional, transforming growth factor beta (TGFbeta)-dependent route to activate the alphaPDGFR is dependent on PDGF-CC. 3. Identify factors that augment the PVR potential of retinal pigment epithelial cells (RPEs). While fibroblasts efficiently induce PVR in our rabbit model, RPE cells do not. This deficiency will be exploited to identify factors that elevate the PVR potential of RPE cells. 4. Screen epiretinal membranes from human PVR donors for expression of factors that promote PVR in the animal model. We will screen epiretinal membranes from human PVR donors for the expression of factors that are critical for PVR in the rabbit model (like alphaPDGFR, activated alphaPDGFR and ligands for this receptor). Together these studies will identify factors that promote PVR and elucidate the relationships between such factors. In addition, our finding will critically evaluate the relevance of the rabbit model to human disease. This information will guide future efforts to develop approaches to prevent and/or treat PVR in humans.