权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Extracellular Matrix and Outflow Resistance

细胞外基质和流出阻力

基本信息

批准号：
8288856
负责人：
Kate E Keller
金额：
$ 22.18万
依托单位：
OREGON HEALTH & SCIENCE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-08-01 至 2015-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8288856
关键词：
Affect Aging Anterior Aqueous Humor Area Attenuated Back Binding Biological Blindness C-terminal Cell surface Cells Cellular Structures Cleaved cell Complex Confocal Microscopy Data Development Disease Disintegrins Endosomes Enzymes Event Extracellular Matrix Extracellular Matrix Degradation Extracellular Space Eye Genes Glaucoma Goals Homeostasis Human Hyaluronan Hyaluronidase Immunofluorescence Microscopy Investigation Lead Life MMP2 gene Matrix Metalloproteinases Messenger RNA Metalloproteases Modeling Molecular Pathway interactions Patients Peptide Hydrolases Perfusion Physiologic Intraocular Pressure Physiological Primary Open Angle Glaucoma Process Proteoglycan RNA Interference Recombinants Recycling Resistance Reverse Transcriptase Polymerase Chain Reaction Role Series Site Structure Symptoms Testing Time Trabecular meshwork structure Work aqueous aqueous humor flow base cell growth regulation cell type extracellular gene synthesis human MMP14 protein inhibitor/antagonist mRNA Transcript Degradation novel pressure public health relevance response uptake versican

项目摘要

Project Summary. Glaucoma is a common blinding disease that affects over 66 million people worldwide and is frequently associated with elevated intraocular pressure (IOP). However, a homeostatic mechanism to adjust elevated IOP must exist since less than 10% of people develop glaucoma. Elevated IOP is caused by increased resistance to aqueous humor outflow through the trabecular meshwork (TM). When TM cells are subjected to sustained elevated IOP, they initiate remodeling of the extracellular matrix (ECM) by releasing specific proteinases including matrix metalloproteinases (MMPs). ECM turnover produces a new, reduced resistance to allow greater aqueous humor outflow through the TM and decrease IOP. Examination of the molecules involved in remodeling, their proteolytic targets and modes and sites of action is critical in order for us to understand how IOP is adjusted. Our long-term goal is to determine the molecular mechanisms by which elevated IOP is homeostatically adjusted in normal eyes. The goal of this current proposal is to further elucidate the function of two ECM components, ADAMTS4 and hyaluronan, and their roles in IOP homeostasis. ADAMTS4 (A Disintegrin and Metalloproteinase with Thrombospondin motifs) is a proteolytic enzyme that degrades ECM components in the TM. ADAMTS4 increases outflow facility in anterior segment perfusion culture suggesting a role for ADAMTS4 in normal homeostatic responses to elevated IOP. Here, we propose a working model whereby ADAMTS4 is activated at specialized cellular structures, then cleaves its target molecules and is internalized into the cell in endosomes. These endosomes may be recycled to the cell surface to release active ADAMTS4 back into the ECM. We will investigate how ADAMTS4 is proteolytically activated and its cellular fate following activation in TM cells. Hyaluronan concentrations in TM decrease during aging and in POAG, which may be due to decreased synthesis, increased degradation or increased cellular hyaluronan uptake. Recently, three genes involved in hyaluronan synthesis and six genes responsible for hyaluronan degradation have been identified and we will investigate their mRNA levels in response to pressure. We will also determine how decreased hyaluronan concentration affects outflow facility in anterior segment perfusion culture. Finally, the effects of hyaluronan concentration on ADAMTS4/MMP expression, localization and/or activation in TM cells will be determined. Investigation into the molecular mechanisms by which ADAMTS4 and hyaluronan are regulated in the TM will provide new information on the complex series of events that leads to homeostatic adjustment of IOP. Studying the molecular details of normal IOP homeostasis should facilitate development of novel therapies targeted at reducing IOP in glaucoma patients.

项目总结。