Mechanisms of Formation of Pseudoexfoliation Material on Human Surgical Lens Capsules

人体手术晶状体囊上假性剥脱材料的形成机制

• 批准号: 9808397
• 负责人: Teresa Borras
• 金额: $ 23.33万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9808397
• 关键词: Address; Affect; Alzheimer' s Disease; Amyloid; Amyloid beta-Protein; Amyloid deposition; Animal Diseases; Animals; Anterior; Anterior Surface of the Lens; Apolipoprotein E; Aqueous Humor; Awareness; Back; Binding Proteins; Blindness; Cataract; Cataract Extraction; Cells; Cessation of life; Characteristics; Ciliary Body; Clinical; Complementary DNA; Confocal Microscopy; Contracts; Country; Data; Deposition; Development; Diagnostic; Disease; Elastic Fiber; Elastin; Environmental Risk Factor; Epithelial Cells; Epithelium; Exfoliation Syndrome; Exposure to; Extracellular Matrix; Eye; FBN1; Fiber; Friction; Gene Delivery; Gene Proteins; Gene Transfer; Genes; Glaucoma; Grant; Histologic; Human; Immunohistochemistry; Iris; Laboratories; Lead; Left; Link; Liquid substance; Logistics; Mechanics; Modeling; Molecular Chaperones; Nature; Operative Surgical Procedures; Ophthalmic examination and evaluation; Ophthalmologist; Ophthalmology; Outcome; Oxidative Stress; Pathologic; Patients; Pharmaceutical Preparations; Physiologic Intraocular Pressure; Physiological; Pigment Epithelium; Play; Production; Proteins; Proteomics; Pupil; Reagent; Resistance; Retinal Ganglion Cells; Role; Senile Plaques; Slide; Specimen; Stress; Surface; Surgeon; System; Systemic disease; Testing; Time; Tissues; Trabecular meshwork structure; Tropoelastin; Viral Vector; Visual Fields; amyloid formation; anterior chamber; aqueous humor flow; base; capsule; experience; experimental study; fibrillin; high intraocular pressure; high reward; high risk; interest; lens; lens capsule; nonhuman primate; novel strategies; optic nerve disorder; pressure; protein complex; small hairpin RNA; stressor; sulfated glycoprotein 2; tissue culture; tool

PROJECT SUMMARY/ ABSTRACT Exfoliation syndrome is a systemic disease of the elastic fibers. The manifestation of this disease in the eye is Pseudoexfoliation Glaucoma (XFG), which is the most common identifiable cause of glaucoma, the most aggressive, and the one harder to treat. The disease is characterized by the formation of amyloid-like deposits by various tissues of the anterior segment of the human eye. In particular, the material is more prominently deposited on the anterior surface of the lens, between the iris and the lens, at the pupillary border. The material is easily recognized by the ophthalmologist during a regular examination and it is dubbed as “a dandruff-like material”. Its presence is the base for the diagnostic of the disease. It is widely accepted that the mechanical friction exerted between the iris and the lens during the opening and closing of the pupil, leads to dislodgement and release of the material into the aqueous humor. During the outflow of this fluid, the material is carried to the trabecular meshwork, causing clogging and a consequent elevated IOP. Proteomics on the composition of the material revealed the presence of a number of components. Among them, some, such as Clusterin (CLU) and ApoE, have been known to be associated with the β-amyloid plaques characteristic of Alzheimer disease. No many studies on XFG have been conducted To date, seven genes have been linked to the XFG, with LOXL1 being the first and best studied. But very little is known about how this material is formed and no attempts to reproduce its formation are available. Also, the XFM has not been observed in any animal species, including nonhuman primates. In this application, we propose to address this need. Because this material is only formed in humans, we devised a novel strategy to conduct the study on human lens, more precisely on the most anterior region, where the material is clinically observed. This region of the lens is routinely peeled off (and discarded) by ophthalmology surgeons during cataract surgery. Termed “lens capsule” (LC), it comprises the 14 µm lens capsule together with the single layer of epithelial cells underneath. Thus, we will develop and characterize these organotypic cultures form the discarded surgical LCs to begin studying how the XFM is formed. We will focus on two major relevant components, CLU and LOXL1. We will modulate their production by gene transfer, and expose them, not only to XFG stressors, but to conditioned media secreted by the lens proximal tissues, specially by the Iris Pigment Epithelium (IPE). We will evaluate formation of XFG-like deposits by confocal microscopy and their effect on the elastin and fibrillin networks in the insoluble ECM by immunohistochemistry. We have initial feasibility data and although important challenges need to be overcome, we believe that the new system could provide an invaluable tool to the field and render important information about the disease. The understanding gained by this study will also open the door to the search of specific treatments of the pseudoexfoliation glaucoma.

项目摘要/摘要