PDGF and PVR

描述（由申请方提供）：复发性玻璃体视网膜病变是一种设盲疾病，现有治疗方案无法满足所有受影响患者的需求。本申请的目的是确定新的治疗靶点，从而指导药物的开发，以预防和/或治疗PVR。血小板衍生生长因子（PDGF）受体的激活？（PDGFR？？）驱动实验性PVR，并与人类的这种疾病有关。抗氧化剂保护兔免于发生PVR并防止玻璃体介导的PDGFR？？活化。此外，玻璃体的独特能力，长期激活PDGFR？是PVR发病机制的内在因素。综上所述，这些观察结果是我们工作假设的基础，玻璃体持续激活PDGFR？？导致活性氧持续升高在目标1的过程中，我们将鉴定那些玻璃体刺激的酶，这些酶是慢性升高ROS和激活PDGFR β所必需的，我们将评估它们作为治疗靶点的潜力。实验性PVR所需的信号传导事件之一是磷脂酰肌醇3激酶（PI 3 K）的活化。两种PDGFR？PDGFR？激活PI 3 K对玻璃体的反应，只有PDGFR？？诱导PVR。我们的工作假设是PDGFR？持续激活Ras，这是PI 3 K持续和强大激活所需的。在目标2的赠款，我们将部署分子和生物化学的方法相结合，以确定这些信号事件，PDGFR？？启动PI 3 K。玻璃体诱导的信号传导事件触发PVR固有的细胞反应，包括增殖、收缩和保护免于凋亡和衰老。例如，构成途径#1的信号传导事件对于这些细胞应答的子集（保护免于凋亡和衰老）是必要的和足够的。相反，虽然途径#1是增殖和收缩所必需的，但它并不足够。在目标3中，我们将使用分子的组合， 和药理学方法来鉴定玻璃体介导的增殖和收缩所需的额外信号传导事件（途径#2）。本提案的目的是：具体目标1确定玻璃体如何慢性激活PDGFR？？。具体目的2研究玻璃体持续激活PI 3 K/Akt的机制。具体目标3鉴定途径#2的成员，这是玻璃体介导的增殖和收缩所需的。该提案的中心假设是，PDGFR？？下游信号传导事件构成PVR的阿喀琉斯之踵。拟议的研究将通过分子解析PVR发病机制中的关键信号事件并评估它们是否是PVR预防的可行靶点来验证这一假设。

DESCRIPTION (provided by applicant): Proliferative vitreoretinopathy is a blinding condition for which available treatment options do not address the needs of all affected patients. This application's objective is to identify new therapeutic targets and thereby guide development of drugs to prevent and/or treat PVR. Activation of platelet-derived growth factor (PDGF) receptor ??? (PDGFR??) drives experimental PVR, and is associated with this disease in humans. Antioxidants protect rabbits from developing PVR and prevent vitreous-mediated activation of PDGFR??. Furthermore, the unique ability of vitreous to chronically activate PDGFR?? is intrinsic to PVR pathogenesis. Taken together, these observations are basis of our working hypothesis that vitreous persistently activates PDGFR?? by causing an enduring elevation of ROS. In the course of aim 1 we will identify those vitreous-stimulated enzymes that are required to chronically elevate ROS and activate PDGFR??, and we will assess their potential as therapeutic targets. One of the signaling events that are required for experimental PVR is activation of phosphatidylinositol 3 kinase (PI3K). While both PDGFR?? and PDGFR?? activate PI3K in response to vitreous, only PDGFR?? induces PVR. Our working hypothesis is that PDGFR?? unceasingly activates Ras, which is required for persistent and robust activation of PI3K. In aim 2 of the grant we will deploy a combination of molecular and biochemical approaches to identify those signaling events by which PDGFR?? engages PI3K. Vitreous-induced signaling events trigger cellular responses intrinsic to PVR that include proliferation, contraction, and protection from apoptosis and senescence. For instance, signaling events that constitute pathway #1 are necessary and sufficient for a subset of these cellular responses (protection from apoptosis and senescence). In contrast, while pathway #1 is necessary for proliferation and contraction, it does not suffice. In aim 3 we will use a combination of molecular and pharmacological approaches to identify the additional signaling events (pathway #2) that are required for vitreous-mediated proliferation and contraction. The aims of this proposal are: Specific Aim 1 Determine how vitreous chronically activates PDGFR??. Specific Aim 2 Investigate the mechanism by which vitreous persistently activates PI3K/Akt. Specific Aim 3 Identify members of pathway #2, which is required for vitreous-mediated proliferation and contraction. This proposal's central hypothesis is that perpetrators of vitreous-dependent activation of PDGFR?? and downstream signaling events constitute an Achilles heel of PVR. The proposed studies will test this hypothesis by molecularly resolving key signaling events in PVR pathogenesis and assessing if they are viable targets for PVR prophylaxis.