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％的接受视网膜重新辅助手术的患者发生增生性玻璃体病（PVR）。 PVR没有有效的非手术疗法，它是NEI的疾病优先级。不知道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，进入玻璃体后，细胞会遇到诱导PVR固有的细胞事件的生长因子。确定促进PVR的玻璃体生长因子并确定其作用机理将公布PVR治疗靶标的聚宝盆。在最后一个赠款期间，我们做出了两个重大发现。首先，尽管血小板衍生的生长因子（PDGF）是玻璃体中存在PVR的患者和动物的生长因子之一，但它们并不是激活PDGFR并促进PVR的唯一生长因子。 PDGF家族（非PDGF）之外的生长因子通过活性氧（ROS）依赖性机制间接激活PDGFR1，我们称为“反式激活”。其次，我们发现PDGF-C是患者和经历PVR的实验动物的主要PDGF亚型，并且纤溶酶是将其加工到Cub和Core域的主要蛋白酶。此外，实验性PVR需要CUB结构域，并诱导嵌入胶原蛋白凝胶中的细胞收缩。该赠款的直接目标是进一步测试PDGF-C的Cub领域正在促进实验性PVR并充分阐明基本机制的想法（AIM 1）；评估PDGFR在实验PVR中的反式激活的贡献（AIM 2）；并测试中和促进PVR相关事件的玻璃体是否是防止实验性PVR的合适策略（AIM 3）。我们的发现将大大促进我们目前对生长因素如何促进PVR的欣赏，并为开发药理（非手术）方法预防和管理PVR所必需的基础。公共卫生相关性：增殖性玻璃体病（PVR）是视网膜重新临床手术失败的主要原因。尽管它的发生相对较低（约5-10％），PVR仍然是一种难以治疗的疾病。除了手术干预外，20-40％的患者无法获得解剖学成功，没有针对患有PVR的个体的治疗方法，因此，对于PVR患者，急需开发基于非手术的疗法。