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：
7797400
负责人：
ROBERT J WORDINGER
金额：
$ 40.58万
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/7797400
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.