PDGF and PVR

描述（由申请人提供）：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%。目前还没有有效的非手术治疗PVR，它是NEI的一个优先考虑的疾病。不知道PVR的分子介质是开发有效治疗PVR的主要障碍。许多实验室的工作表明，生长因子及其受体似乎是PVR的分子介质之一。我们的工作假设是，在进入玻璃体后，细胞遇到了诱导PVR固有细胞事件的生长因子。识别促进PVR的玻璃体生长因子并确定其作用机制，将为PVR的治疗靶点提供新的视角。在上一个拨款期内，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，但它们并不是激活PDGFR和促进PVR的唯一生长因子。PDGF家族外的生长因子（非PDGF）通过依赖活性氧（ROS）的机制间接激活PDGFR1，我们称之为“反激活”。其次，我们发现PDGF- c在PVR患者和实验动物的玻璃体中是主要的PDGF异构体，而纤溶酶是将其加工成CUB和核心结构域的主要蛋白酶。此外，实验PVR需要CUB结构域，它诱导胶原凝胶包埋的细胞收缩。这项资助的直接目标是进一步验证PDGF-C的CUB结构域促进实验性PVR的观点，并充分阐明其潜在机制（目标1）；评估PDGFR转激活在实验性PVR中的作用（目的2）；并测试中和促进PVR相关事件的玻璃体药物是否是预防实验性PVR的合适策略（目的3）。我们的研究结果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的药物（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再植手术失败的主要原因。虽然其发生率相对较低（约5-10%），但PVR仍然是一种难以治疗的疾病。除了20-40%的患者无法获得解剖成功的手术干预外，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方法。

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.