PDGF and PVR

PDGF和PVR

• 批准号: 8303339
• 负责人: Andrius Kazlauskas
• 金额: $ 58.76万
• 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 2013-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8303339
• 关键词: Acute; Animals; Attenuated; Cells; Collagen; Complement; Disease; Enzymes; Event; Extracellular Matrix; Failure; Family; Foundations; Gel; Goals; Grant; Growth Factor; Health; 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; 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）：约5-10%的接受视网膜复位手术的患者发生视网膜变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优先考虑的疾病。不知道PVR的分子介质构成了开发有效治疗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，细胞遇到的生长因子，诱导细胞的PVR内在的事件。鉴定促进PVR的玻璃体生长因子并确定其作用机制将揭示PVR治疗靶点的丰富性。在上一个资助期，我们有两个重大发现。首先，尽管血小板衍生生长因子（PDGF）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家族以外的生长因子（非PDGF）通过活性氧（ROS）依赖性机制间接激活PDGFR 1，我们称之为“反式激活”。其次，我们发现PDGF-C是经历PVR的患者和实验动物的玻璃体中主要的PDGF同种型，并且纤溶酶是将其加工成CUB和核心结构域的主要蛋白酶。此外，CUB结构域是实验性PVR所必需的，并且它诱导包埋在胶原凝胶中的细胞收缩。该资助的近期目标是进一步验证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（目的1）;评估PDGFR反式激活在实验性PVR中的作用（目的2）;并测试促进PVR相关事件的中和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。公共卫生相关性：视网膜脱离复位手术失败的主要原因是玻璃体视网膜病变（PVR）。尽管其发生率相对较低（约5-10%），但PVR仍然是一种难以治疗的疾病。除了手术干预（20-40%的患者未能实现解剖学成功）之外，没有针对患有PVR的个体的治疗，因此迫切需要开发用于患有PVR的患者的基于非手术的疗法。