Fiber Cell Junctions in Normal and Cataractous Lenses

正常和白内障晶状体中的纤维细胞连接

• 批准号: 8135318
• 负责人: M JOSEPH COSTELLO
• 金额: $ 31.97万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 1988
• 资助国家: 美国
• 起止时间: 1988-09-01 至 2014-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8135318
• 关键词: Accounting; Address; Adhesions; Affect; Age; Aging; Architecture; Attention; Biological; Blindness; Caliber; Cataract; Cell Nucleus; Cell fusion; Cell membrane; Cells; Characteristics; Complement; Connexins; Crystallins; Cytoplasm; Cytoplasmic Protein; Deposition; Development; Diagnosis; Elderly; Electron Microscope; Electron Microscopy; Electrons; Evaluation; Excision; Extracellular Protein; Extracellular Space; Fourier Analysis; Future; Goals; Grant; Health; Healthcare Systems; Human; Image; Image Analysis; Imaging Techniques; In Vitro; Incidence; India; Intercellular Junctions; Lens Fiber; Lipid Bilayers; Measures; Membrane; Methods; Microtomy; Molecular; Molecular Weight; Nuclear; Operative Surgical Procedures; Patients; Population; Post-Translational Protein Processing; Prevention strategy; Proteins; Refractive Indices; Relative (related person); Research; Role; Scanning Electron Microscopy; Source; Staging; Structure; Surface; Text; Texture; Theoretical model; Tissues; Transmembrane Transport; Visual; Visual impairment; absorption; age related; aged; base; blind; body density; density; effective therapy; fiber cell; in vivo; lens; light microscopy; light scattering; macula; normal aging; particle; prevent; protein aggregation; protein distribution; success; theories; transmission process

DESCRIPTION (provided by applicant): This competing continuation grant is a request to support further analysis of human age-related nuclear cataracts, the most common form of human cataract that causes visual decline and worldwide blindness. Surgery is the only current treatment, and, while very successful, is a significant burden on healthcare systems and does not address the high incidence of nuclear cataract in aging populations. The long-range goals are to understand the cell biological changes that produce excess light scattering in lens nuclei so that alternative strategies can be devised to prevent the onset or slow the progression lens opacification. The emphasis is on the role of fiber cell junctions in cataract formation. Important progress in the previous grant period includes the identification of 1-4 5m diameter particles that appear to be multiple thin lipid bilayers surrounding nearly spherical globules of cytoplasmic protein. These particles were detected by confocal, multiphoton and bright field light microscopy and by electron microscopy. The particles were found to be more numerous in nuclear cataracts than age-matched transparent donor lenses. A method of quantitative electron absorption was developed to measure the local protein concentration and refractive index of particle interiors compared to adjacent cytoplasm. The ratio gives a measure of the scattering potential. Using Mie scattering theory, these globular particles are potentially very efficient scattering centers producing forward scatter that could affect image formation at the macula. Ultrastructural analysis also demonstrated numerous changes at fiber cell junctions including loss of membrane components, low-density regions (voids), enlargement of extracellular spaces and protein deposits within extracellular spaces. These changes are probably related to protein modification and redistribution during aging and cataract formation. Texturing of the cytoplasm was observed and is probably based on the formation of high molecular weight aggregates. Fourier analysis was used to relate the amount of texturing to the observed opacification of the nucleus. These features appear to be enhanced, including the number of multlamellar particles, in advanced nuclear cataracts from patients in India. Future studies include the characterization of the amount predicted scattering from various types of cellular damage over the entire range from transparent donor lenses to fully opaque nuclear cataracts, thus leading to the mechanism of cataract formation. PUBLIC HEALTH RELEVANCE Cataracts are very common throughout the world and millions of surgical extractions are performed each year to correct visual deficits and blindness caused by cataracts. Surgery at present is the only effective treatment. Our goal is to understand how cells in the lens change during aging and cataract formation so that alternative strategies for prevention and cure can be devised and evaluated.

描述(由申请者提供)：这项竞争性的延续拨款是为了支持对人类年龄相关核性白内障的进一步分析，这是导致视力下降和全球失明的最常见的人类白内障形式。手术是目前唯一的治疗方法，虽然非常成功，但对医疗保健系统来说是一个巨大的负担，而且无法解决老年人口中核性白内障的高发病率问题。长期目标是了解在晶状体核中产生过量光散射的细胞生物学变化，以便可以设计出替代策略来防止晶状体混浊的发生或延缓进展。重点是纤维细胞连接在白内障形成中的作用。在之前的赠款期间取得的重要进展包括鉴定了直径1-4.5米的颗粒，这些颗粒似乎是包裹在近球形细胞质蛋白球体周围的多个薄脂双层。用共聚焦、多光子、明场光学显微镜和电子显微镜对这些颗粒进行了检测。在核性白内障中，这些颗粒比年龄匹配的透明供体晶状体中的颗粒更多。发展了一种定量电子吸收的方法来测量局部蛋白质浓度和颗粒内部相对于相邻细胞质的折射率。这一比率给出了散射势的度量。根据Mie散射理论，这些球状粒子可能是非常有效的散射中心，产生的前向散射可能会影响黄斑处的成像。超微结构分析还显示，纤维细胞连接处发生了许多变化，包括膜成分丢失、低密度区(空洞)、细胞外间隙扩大和细胞外间隙内蛋白质沉积。这些变化可能与衰老和白内障形成过程中蛋白质的修饰和重新分布有关。观察到细胞质的质构，可能是基于高分子量聚集体的形成。使用傅立叶分析将质构量与观察到的核不混浊联系起来。在印度患者的晚期核性白内障中，这些特征似乎得到了增强，包括多层颗粒的数量。未来的研究包括从透明供体晶状体到完全不透明的核性白内障的各种类型的细胞损伤的预测散射量的表征，从而导致白内障的形成机制。与公共健康相关的白内障在世界各地非常常见，每年进行数百万次手术摘除，以纠正由白内障引起的视力障碍和失明。目前手术是唯一有效的治疗方法。我们的目标是了解晶状体细胞在衰老和白内障形成过程中的变化，以便设计和评估替代的预防和治疗策略。