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：
7868657
负责人：
ROBERT J WORDINGER
金额：
$ 14.39万
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 2012-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7868657
关键词：
Address Adenoviruses Anterior Anterior eyeball segment structure Aqueous Humor B-Lymphocytes Biological Blindness Bone Morphogenetic Proteins Cell Line Cells Data Deposition 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 Secretion Proteins 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 overexpression pressure protein function public health relevance 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，升高的眼内压（IOP）通常归因于由近去的近去核基质材料（ECM）积累引起的水性幽默（AH）流出设施降低小梁网（TM）。正常人TM内的ECM沉积与降解之间通常存在平衡。将平衡转向ECM沉积或抑制ECM降解的因素导致ECM的积累。最近的报告表明，转化生长因子22（TGF-22）参与POAG的发病机理。 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。但是，大多数增长因素的生物学作用通常与其他增长因素相抵消。初步发表的我们的实验室数据表明，（a）BMP-4抑制了TGF-22刺激纤连蛋白（FN）和纤溶酶原激活剂抑制剂-1（PAI-1）的分泌，培养的TM细胞和（b）Gremlin，BMP拮抗剂是BMP拮抗剂是在多个青光眼TM细胞系中上调。另外，新的初步数据表明，人类AH和TM组织中存在Gremlin。我们假设（A）BMP抑制TM细胞对ECM相关蛋白分泌的TGF-22刺激，而Gremlin阻断了BMP的抑制作用，从而增加了流出耐药性并升高IOP。已经开发出以下特定目的来检验假设：（1）证明TGF-22上调TM细胞与ECM相关蛋白的合成和分泌，并且该上调被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会阻止TGF-22对ECM蛋白分泌的刺激作用和IOP的分泌，并且（b）在体内使用POC模型和小鼠实验，以证明抑制作用BMP通过GREMLIM的含量会增加流出阻力和IOP升高，因为ECM蛋白的积累。这项研究之所以独一无二，是因为它将解决TGF-22和BMP之间在青光眼发病机理以及BMP拮抗剂Gremlin在人TM中的作用。公共卫生相关性包括我们确定青光眼治疗新目标的能力。公共卫生相关性。青光眼是美国失明的主要原因，是由眼睛的压力升高引起的。升高的眼压是从眼前对流体出口的抗性的结果。这项研究很重要，因为它将检查局部生长因子在控制眼压中的作用，并可能导致青光眼的新治疗方法。