Malformation of the posterior lens sutures is a major cause of increased focal variability and light scatter, and if severe, results in posterior subcapsular cataract and subsequent blindness. It is generally thought that proper migration of differentiating lens fibers, timely detachment and systematic interdigitation of fiber ends plays a crucial role in establishing orderly lens structure and hence, impacts both lens focusing and transparency. The principal investigator of the present proposal has been involved in various studies suggesting that abnormal fiber end migration results in disorderly growth that adversely affects lens function. Although much is known about the arrangement and structure of differentiated lens fibers, significant gaps exist in our understanding of fiber elongation, particularly fiber migration. Here, we propose four hypotheses that address key issues related to fiber migration, including detection of proteins critical to cytoskeletal arrangement and function, fiber attachment to the extracellular matrix, and disruption of cellular and molecular organization during aberrant fiber migration.
The specific aims of the proposal are: 1) to localize the actin-associated proteins caldesmon and fascin and the regulatory protein Cdc42 at posterior migrating fiber ends, 2) to determine if the basal membrane complex (BMC) interaction with the capsule is mediated by a6b1-integrin, a3b1-integrin or both, and if down regulation of integrin expression occurs during the terminal phases of migration, 3) to ascertain whether terminal web proteins such as spectrin and myosin are associated with the F-actin mesh present in maturing lens fibers and determine if the structure is bipolar, and 4) to assess changes in the basal fiber ends during aberrant fiber migration in two models: streptozotocin-induced diabetic rats and Royal College of Surgeons rats. The proposed studies represent a logical extension of our previous work and will advance the field by defining the molecular organization of the BMC during normal and abnormal fiber end migration.
