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Lysosomal Enzymes in Outflow Pathway Physiology and Pathophysiology

流出途径生理学和病理生理学中的溶酶体酶

基本信息

批准号：
9284304
负责人：
Paloma Liton
金额：
$ 45.75万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-06-01 至 2021-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9284304
关键词：
Aging Agreement Alpha Cell Applications Grants Aqueous Humor Biochemical Blindness Caspase Cathepsins Cathepsins B Caveolae Cell Surface Receptors Cell surface Cells Clinical Clinical Trials Collagen Collagen Fiber Connective Tissue Cues Data Degradation Pathway Deposition Disease Drainage procedure Drug Targeting Elastic Fiber Endothelial Cells Environment Enzymes Etiology Extracellular Matrix Eye Functional disorder Future Glaucoma Ground Substance Human Image In Vitro Laboratories Matrix Metalloproteinases Mechanics Mediating Modeling Molecular Mus Nature Ocular Hypertension Pathogenesis Pathway interactions Patients Peptide Hydrolases Pharmacology Physiologic Intraocular Pressure Physiology Play Primary Open Angle Glaucoma Proteomics Resistance Retinal Ganglion Cells Risk Role Route Serine Protease Testing Time Tissues Trabecular meshwork structure Transforming Growth Factor Beta 2 Transforming Growth Factor beta Work base carboxypeptidase C extracellular in vivo novel novel therapeutics prevent protein B uptake

项目摘要

SUMMARY Defective aqueous humor (AH) drainage through the trabecular meshwork (TM) / Schlemm's cannal (SC) conventional outflow pathway is usually associated to elevated intraocular pressure (IOP), and hence, increased risk for developing glaucoma, a blinding disease second leading cause of permanent blindness in the US. The nature of such resistance to AH outflow is far from being elucidated. The TM consists of sheets of connective tissue beams lined by TM endothelial cells. Each beam is composed of a central elastic core surrounded by collagen fibers embedded in a ground substance. The glaucomatous outflow pathway is characterized by thickening of the trabecular lamellae and accumulation of long-spacing collagen bundles and elastic fiber sheaths, which is presumed to stiffen the TM and prevent the tissue to respond to mechanical cues. The exact causes underlying the deposit of extracellular material (ECM) and thickening of the beams remain unknown; but it is likely a consequence of excessive synthesis of ECM components, decreased proteolytic degradation, or both. Matrix metalloproteinases (MMPs) have been historically believed to be the major proteases involved in ECM degradation; however, emerging evidence indicates that while MMPs play a critical role in initiating ECM degradation in the extracellular environment, other proteases or the coordinated action of several types of proteases (i.e. cysteine and serine proteases) are responsible for the bulk matrix degradation, occurring pericellularly and intracellularly in the lysosomal compartment, associated to lysosomal cathepsins. In agreement, studies conducted in our laboratory have clearly demonstrated the constitutive cell surface expression and secretion of cathepsin B (CTSB) in TM cells and its participation in the endocytic uptake and intralysosomal degradation of native and denature collagens. Here we propose to investigate for the first time the contribution of a CTSB-mediated pericellular and intracellular ECM degradative pathway in TM cells and the effect on outflow physiology. We hypothesize that CTSB plays a critical role in ECM remodeling and outflow physiology by initiating a proteolytic cascade leading to the pericellular and intracellular degradation of ECM components in TM cells. We further hypothesize that modulation of CTSB activity may represent a novel therapeutic strategy in glaucoma. To test this hypothesis, we will (1) demonstrate that CTSB associates with caveolae and initiates a proteolytic cascade resulting in the partial degradation of ECM components; (2) determine the cell surface receptors participating in of ECM components in TM cells; and (3) evaluate the effects of modulating CTSB activity in outflow pathway function of murine glaucoma models.

总结