PDGF and PVR

PDGF和PVR

• 批准号: 7087790
• 负责人: ANDRIUS KAZLAUSKAS
• 金额: $ 47.85万
• 依托单位: SCHEPENS EYE RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-08-01 至 2009-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7087790
• 关键词: biological signal transduction; cell growth regulation; cellular pathology; clinical research; disease /disorder etiology; disease /disorder model; gene expression; genetic regulation; growth factor receptors; human tissue; intermolecular interaction; laboratory rabbit; ligands; molecular pathology; northern blottings; phosphorylation; phosphotransferases; platelet derived growth factor; proliferative vitreoretinopathy; protein isoforms; protein structure function; retinal pigment epithelium; transforming growth factors; western blottings

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.

描述（由申请人提供）：我们在上一个资助期的发现包括血小板衍生生长因子（PDGF）受体（PDGFR）存在于人类增殖性玻璃体视网膜病变（PVR）供体的视网膜前膜中，并且PDGFR是在该疾病的兔模型中发展PVR所必需的。我们将继续研究 PDGF 在 PVR 中的作用，如以下具体目标所述： 1. 研究为什么 alphaPDGFR 比 betaPDGFR 更能引起 PVR。在兔 PVR 模型中，表达 alphaPDGFR 的细胞比表达 betaPDGFR 的相同细胞更有效地诱导 PVR。我们将通过使用 alpha 和 betaPDGFR 的嵌合体来鉴定 alphaPDGFR 的区域，该区域使 betaPDGFR 能够诱导 PVR。 2. 检验 TGFbeta 通过 PDGF-CC 激活 alphaPDGFR 的假设。 PDGFR 的激活是 兔 PVR 的先决条件，为此，我们将测试我们最近发现的非常规、转化生长因子 β (TGFβ) 依赖性激活 alphaPDGFR 的途径是否依赖于 PDGF-CC。 3. 确定增强视网膜色素上皮细胞 (RPE) PVR 潜力的因素。虽然成纤维细胞在我们的兔子模型中有效诱导 PVR，但 RPE 细胞却不能。将利用这一缺陷来识别提高 RPE 细胞 PVR 潜力的因素。 4. 筛选来自人类 PVR 供体的视网膜前膜，以了解在动物模型中促进 PVR 的因子的表达。我们将筛选来自人类 PVR 供体的视网膜前膜，以了解对兔模型中 PVR 至关重要的因子（如 alphaPDGFR、激活的 alphaPDGFR 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，我们的发现将严格评估兔子模型与人类疾病的相关性。这些信息将指导未来开发预防和/或治疗人类 PVR 的方法。