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.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
1R01EY014902-01A2
Application #
6922681
Study Section
Special Emphasis Panel (ZRG1-AED (01))
Program Officer
Liberman, Ellen S
Project Start
2005-05-01
Project End
2009-04-30
Budget Start
2005-05-01
Budget End
2006-04-30
Support Year
1
Fiscal Year
2005
Total Cost
$210,466
Indirect Cost
Name
Rush University Medical Center
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
068610245
City
Chicago
State
IL
Country
United States
Zip Code
60612
Joy, Anita; Al-Ghoul, Kristin J (2014) Basal membrane complex architecture is disrupted during posterior subcapsular cataract formation in Royal College of Surgeons rats. Mol Vis 20:1777-95
Joy, Anita; Mohammed, Tabraiz A; Al-Ghoul, Kristin J (2010) Abnormal fiber end migration in Royal College of Surgeons rats during posterior subcapsular cataract formation. Mol Vis 16:1453-66
Al-Ghoul, Kristin J; Lindquist, Timothy P; Kirk, Spencer S et al. (2010) A novel terminal web-like structure in cortical lens fibers: architecture and functional assessment. Anat Rec (Hoboken) 293:1805-15
Joy, Anita; Currie, Matthew S; Donohue, Sean T et al. (2009) Aberrant basal fiber end migration underlies structural malformations in a streptozotocin-induced diabetic rat model. Exp Eye Res 89:344-57
Lu, Jeffrey Y; Mohammed, Tabraiz A; Donohue, Sean T et al. (2008) Distribution of basal membrane complex components in elongating lens fibers. Mol Vis 14:1187-203
Al-Khudari, Samer; Donohue, Sean T; Al-Ghoul, Walid M et al. (2007) Age-related compaction of lens fibers affects the structure and optical properties of rabbit lenses. BMC Ophthalmol 7:19