BMP Regulation of TGF-b2 in the Trabecular Meshwork

BMP 对小梁网中 TGF-b2 的调节

基本信息

批准号：
7690536
负责人：
ROBERT J WORDINGER
金额：
$ 6.5万
依托单位：
UNIVERSITY OF NORTH TEXAS HLTH SCI CTR
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-04-01 至 2013-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7690536
关键词：
Address Adenoviruses Anterior Anterior eyeball segment structure Appendix Aqueous Humor B-Lymphocytes Biological Blindness Bone Morphogenetic Proteins Cell Line Cells Data Deposition Elevation Equilibrium Extracellular Matrix Eye Fibronectins Glaucoma Growth Factor Human Laboratories Lead Liquid substance Modeling Mus Organ Culture Techniques Pathogenesis Patients Physiologic Intraocular Pressure Plasminogen Activator Inhibitor 1 Plasminogen Inactivators Primary Open Angle Glaucoma Protein Overexpression Protein Secretion Proteins Public Health Publications Publishing Regulation Reporting Resistance Role Signal Pathway System Testing Tissues Trabecular meshwork structure Transforming Growth Factor Beta 2 Transforming Growth Factors United States Up-Regulation bone morphogenetic protein 4 ex vivo perfusion expression vector in vivo mouse model pressure protein function research study

项目摘要

DESCRIPTION (provided by applicant): In primary open-angle glaucoma (POAG), elevated intraocular pressure (IOP) is often attributed to diminished aqueous humor (AH) outflow facility caused by accumulation of extracellular matrix material (ECM) in the juxtacanicular region of the trabecular meshwork (TM). A balance normally exists between ECM deposition and degradation within the normal human TM. Factors that shift the balance towards either ECM deposition or inhibition of ECM degradation results in accumulation of ECM. Recent reports indicate that transforming growth factor-22 (TGF-22) is involved in the pathogenesis of POAG. TGF-22 is elevated in the AH of patients with POAG. In addition, using both cultured TM cells and a perfused anterior eye organ culture model (POC), TGF-22 increased synthesis and deposition of ECM proteins. However, the biological actions of most growth factors are often counterbalanced by other growth factors. Preliminary published data from our laboratory indicates that (a) BMP-4 inhibits TGF-22 stimulation of fibronectin (FN) and plasminogen activator inhibitor-1 (PAI-1) secretion by cultured TM cells and (b) gremlin, a BMP antagonist is upregulated in multiple glaucomatous TM cell lines. In addition new preliminary data indicates that gremlin is present in human AH and TM tissues. We hypothesize that (a) BMPs inhibit TGF-22 stimulation of ECM-related protein secretion by TM cells and (b) gremlin blocks the inhibitory action of BMPs resulting in increased outflow resistance and elevated IOP. The following specific aims have been developed to test the hypothesis: (1) demonstrate that TGF-22 upregulates the synthesis and secretion of ECM-related proteins by TM cells and this upregulation is inhibited by BMP-4, (2) determine the signaling pathway used by BMPs to block TGF-22 upregulation of ECM-related proteins in TM cells; (3) utilize (a) the POC model to demonstrate that BMPs block the stimulatory effect of TGF-22 on both secretion of ECM proteins and elevation of IOP and (b) utilize both the POC model and mouse in vivo experiments to demonstrate that inhibition of BMP via gremlin results in increased outflow resistance and elevated IOP due to accumulation of ECM proteins. This study is unique because it will address the relationships between TGF-22 and BMPs in the pathogenesis of glaucoma as well as the role of the BMP antagonist gremlin in the human TM. Public health relevance includes our ability to identify new targets for the treatment of glaucoma. PUBLIC HEALTH RELEVANCE. Glaucoma is a leading cause of blindness in the United States and is caused by elevated pressure in the eye. Elevated eye pressure is a result of a resistance to the exit of fluid from the front of the eye. This study is relevant because it will examine the role of local growth factors in the control of eye pressure and may lead to new treatments for glaucoma.

描述（由申请人提供）：在原发性开角型青光眼 (POAG) 中，眼内压 (IOP) 升高通常归因于房水 (AH) 流出设施减少，这是由于细胞外基质物质 (ECM) 在眼角旁区域积聚所致。小梁网（TM）。正常人 TM 内 ECM 沉积和降解之间通常存在平衡。将平衡转向 ECM 沉积或抑制 ECM 降解的因素会导致 ECM 积累。最近的报告表明转化生长因子-22 (TGF-22) 参与 POAG 的发病机制。 POAG 患者的 AH 中 TGF-22 升高。此外，使用培养的 TM 细胞和灌注的前眼器官培养模型 (POC)，TGF-22 增加了 ECM 蛋白的合成和沉积。然而，大多数生长因子的生物作用常常被其他生长因子抵消。我们实验室初步发表的数据表明，(a) BMP-4 抑制培养 TM 细胞分泌的 TGF-22 刺激纤连蛋白 (FN) 和纤溶酶原激活物抑制剂-1 (PAI-1) 和 (b) gremlin（一种 BMP 拮抗剂）在多种青光眼 TM 细胞系中上调。此外，新的初步数据表明，gremlin 存在于人类 AH 和 TM 组织中。我们假设 (a) BMP 抑制 TGF-22 刺激 TM 细胞分泌 ECM 相关蛋白，(b) gremlin 阻断 BMP 的抑制作用，导致流出阻力增加和 IOP 升高。为了检验这一假设，我们制定了以下具体目标：(1) 证明 TGF-22 上调 TM 细胞 ECM 相关蛋白的合成和分泌，并且这种上调被 BMP-4 抑制，(2) 确定信号通路BMP 用于阻断 TM 细胞中 ECM 相关蛋白的 TGF-22 上调； (3) 利用 (a) POC 模型证明 BMP 阻断 TGF-22 对 ECM 蛋白分泌和 IOP 升高的刺激作用，以及 (b) 利用 POC 模型和小鼠体内实验来证明抑制作用由于 ECM 蛋白的积累，通过 gremlin 处理 BMP 会导致流出阻力增加和 IOP 升高。这项研究的独特之处在于它将探讨 TGF-22 和 BMP 在青光眼发病机制中的关系以及 BMP 拮抗剂 gremlin 在人类 TM 中的作用。公共卫生相关性包括我们确定青光眼治疗新靶点的能力。公共卫生相关性。青光眼是美国失明的主要原因，是由眼压升高引起的。眼压升高是由于眼睛前部液体排出受到阻力而导致的。这项研究具有重要意义，因为它将检查局部生长因子在控制眼压中的作用，并可能带来青光眼的新治疗方法。