The influence of capsule composition on lens biology

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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.