The influence of capsule composition on lens biology

胶囊成分对晶状体生物学的影响

• 批准号: 7463868
• 负责人: MELINDA K DUNCAN
• 金额: $ 37.49万
• 依托单位: UNIVERSITY OF DELAWARE
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-12-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7463868
• 关键词: Affect; Animals; Anterior; Apoptosis; Artificial Implants; Basement membrane; Binding; Biology; Cataract; Cell surface; Cells; Cellular biology; Cessation of life; Charge; Class; Collagen; Collagen Type IV; Communication; Cornea; Crystalline Lens; Defect; Development; Diffusion; Disease; ECM receptor; Environment; Epithelial; Epithelial Cells; Epithelium; Excision; Extracellular Matrix Protein Gene; Eye; Fiber; Fluorescence Recovery After Photobleaching; Genes; Grant; Growth Factor; Hereditary nephritis; Homeostasis; Human; Integrins; Lens Fiber; Mediating; Molecular; Molecular Abnormality; Mus; Mutation; Nature; Pathology; Permeability; Personal Satisfaction; Phenotype; Play; Property; Proteins; Protocols documentation; Public Health; Role; Signal Transduction; Staging; Testing; Virus; Vision; Vitreous humor; aqueous; capsule; cell capsule; epithelial to mesenchymal transition; in vivo; lens; lens capsule; prevent; response

DESCRIPTION (provided by applicant): The lens capsule is a thickened basement membrane that completely surrounds the lens from its earliest developmental stages until death. It is well established that the lens capsule is crucial for lens development and function and lens capsule pathologies can threaten vision. An established function of the lens capsule is to serve as a selectable filter between the lens and the ocular environment, however, relatively little is known about the properties of this filter. During the prior grant cycle, we developed a robust fluorescence recovery after photobleaching (FRAP) protocol which can evaluate both the ability of molecules to enter the lens capsule and quantitatively determine their diffusion coefficient. In the first aim of this application, we propose to use FRAP to elucidate the molecular properties of the normal lens capsule filter. It is also known that mutations in extracellular matrix (ECM) protein genes result in cataract. The second aim tests the hypothesis that alterations in collagen IV activate the unfolded protein response leading to cataract. Another established function of the lens capsule is to engage ECM receptors on lens cells, providing both a structural anchor for the cell and inducing cell signaling cascades crucial for lens cell phenotype. Integrins are a major class of ECM receptors present on lens cells and ¿1 integrin is the major b-integrin subunit expressed by the lens. In the prior grant cycle, we created mice lacking ¿1 integrin in either all lens cells or just lens fibers to test the hypothesis that ¿1-integrin is important for lens cell/lens capsule communication. The phenotypes of the resulting animals are quite distinct and we now propose in specific aim three to elucidate the function of ¿1-integrin in the in vivo lens by analyzing the molecular abnormalities seen in these animals. Public Health Relevance: The lens capsule is important for the function of the normal ocular lens, although little is known about how diseases affecting the lens capsule result in lens abnormalities. Further, the lens capsule is usually retained in the eye after the surgical removal of cataracts to both support the implanted artificial replacement lens and to serve as a barrier, between the anterior and posterior portions of the eye, although the resulting abnormal lens cell/capsule interactions often result in secondary cataract. A complete understanding of the communication between lens cells and the capsule are crucial to develop treatments to prevent secondary cataract.

描述(申请人提供)：晶状体囊是一层增厚的基底膜，从晶状体最早的发育阶段到死亡，它完全包围着晶状体。众所周知，晶状体囊膜对晶状体的发育和功能至关重要，晶状体囊膜病变会威胁视力。晶状体胶囊的既定功能是充当晶状体和眼环境之间的可选择滤光片，然而，对该滤光片的特性知之甚少。在之前的资助周期中，我们开发了一种稳健的光漂白后荧光恢复(FRAP)方案，该方案可以评估分子进入晶状体囊的能力，并定量确定它们的扩散系数。在这一应用的第一个目的中，我们建议使用FRAP来阐明正常晶状体胶囊滤光片的分子性质。细胞外基质(ECM)蛋白基因的突变也是已知的导致白内障的原因。第二个目的是测试IV型胶原蛋白改变激活未折叠蛋白反应从而导致白内障的假设。晶状体囊膜的另一个既定功能是与晶状体细胞上的ECM受体结合，为细胞提供结构锚，并诱导对晶状体细胞表型至关重要的细胞信号级联反应。整合素是存在于晶状体细胞上的一类主要的细胞外基质受体，1整合素是晶状体表达的主要b-整合素亚基。在之前的资助周期中，我们建立了在所有晶状体细胞或仅在晶状体纤维中缺乏整合素的小鼠，以测试晶状体细胞/晶状体囊通讯中整合素缺失的假设。由此产生的动物的表型相当不同，我们现在提出的具体目标三是通过分析在这些动物中看到的分子异常来阐明1-整合素在体内晶状体中的功能。公共卫生相关性：晶状体囊膜对正常眼晶状体的功能很重要，尽管人们对影响晶状体囊膜的疾病如何导致晶状体异常知之甚少。此外，在手术摘除白内障后，晶状体囊通常保留在眼睛内，既支持植入的人工晶状体，又充当眼睛前部和后部之间的屏障，尽管由此产生的晶状体细胞/囊膜异常相互作用经常导致继发性白内障。完全了解晶状体细胞和晶状体囊之间的联系对于开发预防继发性白内障的治疗方法至关重要。