PDGF and PVR

PDGF和PVR

• 批准号: 7649729
• 负责人: Andrius Kazlauskas
• 金额: $ 58.86万
• 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 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7649729
• 关键词: Acute; Animals; Attenuated; Cells; Collagen; Complement; Disease; Enzymes; Event; Extracellular Matrix; Failure; Family; Foundations; Gel; Goals; Grant; Growth Factor; Individual; Intervention; Mediator of activation protein; Molecular; Operative Surgical Procedures; Oryctolagus cuniculus; PDGFRB gene; Patients; Peptide Hydrolases; Phase; Plasmin; Platelet-Derived Growth Factor; Process; Production; Proliferative Vitreoretinopathy; Protease Inhibitor; Protein Isoforms; Reactive Oxygen Species; Recombinants; Retinal; Retinal Detachment; Role; Signal Transduction; Testing; Transactivation; Work; base; cytokine; effective therapy; experience; platelet-derived growth factor C; prevent; public health relevance; receptor; small hairpin RNA; success; therapeutic target

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.

描述（由申请人提供）：大约 5-10% 接受视网膜再附着手术的患者会出现增殖性玻璃体视网膜病变 (PVR)。 PVR 尚无有效的非手术治疗方法，是 NEI 的重点疾病。不了解 PVR 的分子介质是开发 PVR 有效疗法的主要障碍。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，细胞进入玻璃体后会遇到生长因子，从而诱导 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 治疗靶点的聚宝盆。在上一个资助期内，我们取得了两项重大发现。首先，尽管血小板衍生生长因子（PDGF）是存在于经历 PVR 的患者和动物玻璃体中的生长因子之一，但它们并不是激活 PDGFR 并促进 PVR 的唯一生长因子。 PDGF 家族以外的生长因子（非 PDGF）通过活性氧 (ROS) 依赖性机制（我们称之为“反式激活”）间接激活 PDGFR1。其次，我们发现PDGF-C是经历PVR的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CUB和核心结构域的主要蛋白酶。此外，实验性 PVR 需要 CUB 结构域，它会诱导胶原凝胶中嵌入的细胞收缩。本次资助的近期目标是进一步检验 PDGF-C 的 CUB 结构域正在促进实验性 PVR 的想法，并充分阐明其潜在机制（目标 1）；评估 PDGFR 反式激活在实验性 PVR 中的贡献（目标 2）；并测试中和促进 PVR 相关事件的玻璃体制剂是否是预防实验性 PVR 的合适策略（目标 3）。我们的研究结果将大大推进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。公众健康相关性：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。除了手术干预外（20-40% 的患者未能获得解剖学成功），患有 PVR 的个体没有治疗方法，因此迫切需要为患有 PVR 的患者开发非手术疗法个人录像。