Integrin Signaling in the Trabecular Meshwork

小梁网中的整合素信号传导

• 批准号: 8059627
• 负责人: Donna M Peters
• 金额: $ 35.27万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-01 至 2013-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8059627
• 关键词: Actins; Active Sites; Affect; African American; Amino Acids; Anterior; Aqueous Humor; Binding; Binding Proteins; Binding Sites; Blindness; Cell Adhesion; Cells; Cytoplasmic Tail; Cytoskeleton; Data; Down-Regulation; Effectiveness; Event; Extracellular Matrix; Fibronectins; Genes; Glaucoma; Goals; Grant; Heparin; Human; Integrin Binding; Integrin Signaling Pathway; Integrins; Laboratories; Lead; Lentivirus Vector; Ligands; Lymphocyte Activation; Molecular; Monkeys; Monomeric GTP-Binding Proteins; Mutation; Organ Culture Techniques; Peptides; Perfusion; Physiologic Intraocular Pressure; Physiological; Play; Property; Regulation; Research; Retinal Ganglion Cells; Risk Factors; Role; Signal Pathway; Signal Transduction; Testing; Trabecular meshwork structure; base; design; paxillin; public health relevance; receptor; therapeutic target

DESCRIPTION (provided by applicant): This is a new application for a R01. The long-term objective of this grant is to identify integrin signaling mechanisms that can be used as therapeutic targets to control and lower intraocular pressure. 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. Studies from our laboratory have shown that the signaling properties of bioactive fragments from the extracellular matrix (ECM) and their receptors (integrins) can be used to regulate the contractility of the TM and increase outflow facility in cultured anterior segments. In particular we have shown that a bioactive domain from fibronectin called the HepII domain activates a ?4?1 integrin signaling pathway that decreases cell contractility in cultured TM cells. Our preliminary data strongly supports the hypothesis that manipulation of integrin signaling pathways in the TM that modify cellular contractility can be used to regulate outflow facility. The objective of this research is to identify possible ways to target integrin signaling pathways in the TM in order to increase outflow facility. To this end, we propose three approaches to activate the ?4?1 signaling pathway in cultured anterior segments. First, use lentiviral vectors to express a mini-HepII gene in the TM. Second, over express a constitutively activated ?4 integrin subunit in the TM. Third, express peptides from the cytoplasmic domain of the ?4-subunit or the integrin binding protein, paxillin which disrupt cell adhesion and decrease cell contractility. The studies proposed in this application will not only enhance our understanding of the role of integrin signaling in the TM, but it will identify new ways to target cell contractility in the TM. 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. Increased intraocular pressure (IOP) is a common risk factor for glaucoma. The goal of this project is to identify signaling pathway(s) that can be activated to reduce IOP and be used as potential targets to treat glaucoma.

描述（由申请人提供）：这是R01的新应用程序。该赠款的长期目标是确定可以用作控制和降低眼内压的治疗靶标的整联蛋白信号传导机制。绿哥膜导致视网膜神经节细胞的不可逆转损失，全世界大约有6700万人。由于小梁网（TM）的水性幽默流出降低，它们通常与眼内压（IOP）升高有关。尽管已知许多生理因素可以调节流出设施，但出现作为流出设施的重要调节机制的关键因素之一是TM的收缩特性。目前，尚不清楚哪些分子事件调节TM中的收缩力。我们实验室的研究表明，来自细胞外基质（ECM）的生物活性片段的信号传导特性及其受体（整联蛋白）可用于调节TM的收缩力并增加培养的前部部分中的流出设施。特别是我们已经表明，来自纤连蛋白的生物活性结构域称为HEPII结构域会激活A？4？1整合素信号传导途径，可降低培养的TM细胞中细胞收缩性。我们的初步数据强烈支持以下假设：TM中整合素信号通路的操纵可以使用细胞收缩力来调节流出设施。这项研究的目的是确定靶向TM中整合素信号通路以增加流出设施的可能方法。为此，我们提出了三种激活培养的前段中的信号传导途径的方法。首先，使用慢病毒载体在TM中表达一个迷你-HEPII基因。其次，在TM中超出组成型激活的？4整合素亚基。第三，来自？4-亚基的细胞质结构域或整联蛋白结合蛋白，帕克西林的表达肽，破坏细胞粘附并降低细胞收缩力。本应用程序中提出的研究不仅会增强我们对整联蛋白信号在TM中的作用的理解，而且还将确定靶向TM中细胞收缩力的新方法。 公共卫生相关性：青光眼是美国盲目的第二大最常见原因，也是非裔美国人中最常见的失明原因。眼内压力（IOP）是青光眼的常见危险因素。该项目的目的是确定可以激活以减少IOP并用作治疗青光眼的潜在靶标的信号通路。