PDGF and PVR

描述(申请人提供)：增殖性玻璃体视网膜病变(PVR)发生在接受视网膜再附着手术的患者中约5%-10%。PVR目前尚无有效的非手术治疗方法，是NEI的首选疾病。不了解PVR的分子介质是开发有效的PVR治疗方法的主要障碍。许多实验室的研究表明，生长因子及其受体似乎是PVR的分子介质。我们的工作假设是，当进入玻璃体时，细胞会遇到生长因子，这些生长因子会引发PVR固有的细胞事件。识别促进PVR的玻璃体生长因子并确定其作用机制将揭示PVR治疗靶点的丰富多彩。在上一次授权期内，我们有了两项重大发现。首先，尽管血小板衍生生长因子(PDGFs)是PVR患者和动物玻璃体中存在的生长因子之一，但它们并不是唯一激活PDGFR和促进PVR的生长因子。PDGF家族以外的生长因子(非PDGFs)通过一种活性氧簇(ROS)依赖的机制间接激活PDGFR1，我们称之为“反式激活”。其次，我们发现PDGF-C是PVR患者和实验动物玻璃体中主要的PDGF亚型，而纤溶酶是将其加工成幼体和核心区的主要蛋白酶。此外，Cub结构域是实验性PVR所必需的，它可以诱导胶原凝胶中的细胞收缩。这笔赠款的直接目标是进一步测试PDGF-C的Cub结构域促进实验性PVR的想法，并充分阐明潜在的机制(目标1)；评估PDGFR反式激活在实验性PVR中的作用(目标2)；以及测试促进PVR相关事件的玻璃体中和剂是否是预防实验性PVR的合适策略(目标3)。我们的发现将大大提高我们目前对生长因子如何促进PVR的认识，并为开发预防和管理PVR的药理学(非手术)方法奠定必要的基础。公共卫生相关性：增殖性玻璃体视网膜病变(PVR)是孔源性视网膜脱离视网膜复位手术失败的主要原因。虽然PVR的发生率相对较低(约5-10%)，但它仍然是一种难以治疗的疾病。除了手术干预，20-40%的患者未能取得解剖上的成功，还没有针对PVR患者的治疗方法，因此迫切需要为PVR患者开发非手术治疗。

DESCRIPTION (provided by applicant): Proliferative vitreoretinopathy (PVR) occurs in approximately 5-10% of the patients that undergo retinal re-attachment surgery. There is no effective non-surgical therapy for PVR, and it is a disease priority of the NEI. Not knowing the molecular mediators of PVR constitutes a major roadblock in developing effective therapies for PVR. Work from many labs indicates that growth factors and their receptors appear to be among the molecular mediators of PVR. Our working hypothesis is that upon entry into the vitreous, cells encounter growth factors that induce cellular events intrinsic to PVR. Identifying the vitreal growth factors that promote PVR and determining their mechanism of action will unveil a cornucopia of therapeutic target for PVR. In the last grant period we made two major discoveries. First, although platelet-derived growth factors (PDGFs) were among the growth factors present in the vitreous of patients and animals experiencing PVR, they were not the only growth factors that activated PDGFR and promoted PVR. Growth factors outside of the PDGF family (non-PDGFs) indirectly activated PDGFR1 by a reactive oxygen species (ROS)-dependent mechanism that we are calling "transactivation". Second, we discovered that PDGF-C was the predominant PDGF isoform in the vitreous of patients and experimental animals experiencing PVR, and that plasmin was the major protease that processed it to the CUB and core domains. Furthermore, the CUB domain was required for experimental PVR, and it induced contraction of cells embedded in collagen gels. The immediate goals of this grant are to further test the idea that the CUB domain of PDGF-C is promoting experimental PVR, and to fully elucidate the underlying mechanism (aim 1); to assess the contribution of transactivation of the PDGFR in experimental PVR (aim 2); and test if neutralizing vitreal agents that promote PVR-related events is a suitable strategy to prevent experimental PVR (aim 3). Our findings will substantially advance our current appreciation of how growth factors promote PVR and establish the foundation necessary to develop pharmacological (non-surgical) approaches to prevent and manage PVR. PUBLIC HEALTH RELEVANCE: Proliferative vitreoretinopathy (PVR) is the major cause for failure of retinal reattachment surgery for rhegmatogenous retinal detachment. While its occurrence is relatively low (approximately 5-10%) PVR remains a difficult disease to treat. With the exception of surgical intervention, for which 20-40% of the patients fail to achieve anatomical success, there is no treatment for individuals afflicted with PVR, and hence there is an acute need to develop non-surgical-based therapies for patients with PVR.