Control of Trabecular Meshwork Cytoskeleton

描述（由申请人提供）：这是EY017006的竞争性更新。这项资助的长期目标是确定细胞基质信号传导机制，可用作控制类固醇诱导的青光眼的治疗靶点。青光眼导致视网膜神经节细胞的不可逆损失，影响全球约6700万人。它们通常与眼内压（IOP）水平升高相关，这是由于小梁网（TM）的房水流出减少。尽管已知许多生理因素调节流出功能，但作为流出功能的重要调节机制出现的关键因素之一是TM的收缩特性。目前，还不清楚是什么分子事件调节TM的收缩性。细胞外基质（ECM）蛋白及其受体（整合素）的信号传导特性在调节细胞收缩性中起着关键作用，我们提出这些信号传导途径中一种或多种组分的激活可能是导致类固醇诱导的青光眼中观察到的交联肌动蛋白网络（CLANs）形成的原因。我们的研究表明，地塞米松在CLAN形成过程中激活了这一通路。在这次竞争性更新中，我们计划确定流出设施的变化是否与以下水平相关？v？3在类固醇存在和不存在的情况下培养的前段中的整合素信号传导。我们还计划确定地塞米松用于激活？v？3整合素。为了帮助识别可能被类固醇上调的成分，我们计划使用定量磷酸蛋白质组学来识别整合素信号通路的成分，这些成分不受类固醇治疗的调节，并在培养的TM细胞中被整合素和CD47激活。这些研究应显示整合素信号通路是否可能参与类固醇诱导的青光眼。 公共卫生相关性：青光眼是美国第二大常见的致盲原因，也是非洲裔美国人最常见的致盲原因。由于缺乏明确的细胞培养系统，试图了解这种疾病的原因受到阻碍。该项目的目标是确定类固醇诱导的青光眼（SIG）期间激活的信号通路，从而确定潜在的治疗靶点以减少SIG。

DESCRIPTION (provided by applicant): This is a competitive renewal for EY017006. The long-term objective of this grant is to identify cell-matrix signaling mechanisms that can be used as therapeutic targets to control steroid induced glaucoma. The glaucomas, which lead to irreversible loss of retinal ganglion cells, affect approximately 67 million people worldwide. They are commonly associated with elevated levels of intraocular pressure (IOP) due to a reduction in aqueous humor outflow from the trabecular meshwork (TM). Although a number of physiological factors are known to regulate outflow facility, one of the key factors that have emerged as an important regulatory mechanism for outflow facility is the contractile properties of the TM. At the present, it is unclear what molecular events regulate contractility in the TM. It is well established that the signaling properties of extracellular matrix (ECM) proteins and their receptors (integrins) play a critical role in regulating cell contractility and we proposed that activation of one or more of the components in these signaling pathways may be responsible for the formation of cross-linked actin networks (CLANs) observed in steroid induced glaucoma. Our studies have shown that dexamethasone activates this pathway during the formation of CLANs. In this competitive renewal we plan to determine if changes in outflow facility correlate with the levels of ?v?3 integrin signaling in cultured anterior segments in the presence and absence of steroids. We also plan to identify the signaling pathways utilized by dexamethasone to activate ?v?3 integrins. To aid in the identification of components that may be upregulated by steroids we plan to use quantitative phosphoproteomics to identify components of the integrin signaling pathways that are unregulated by steroid treatment and activated by both integrin and CD47 in TM cells in culture. These studies should show whether integrin signaling pathway(s) could be involved in steroid induced glaucoma. PUBLIC HEALTH RELEVANCE: Glaucoma is the second most common cause of blindness in the U.S. and the most common cause of blindness among African-Americans. Attempts to understand the cause(s) of this disease have been hampered by the lack of well defined cell culture systems. The goal of this project is to identify the signaling pathway(s) activated during steroid induced glaucoma (SIG) so we identify potential therapeutic targets to reduce SIG.