Shihan, Mahbubul H.2021-03-112021-03-112020https://udspace.udel.edu/handle/19716/28822Posterior capsular opacification (PCO), one of the major complications of cataract surgery, occurs when lens epithelial cells (LCs) left behind post cataract surgery (PCS) undergo epithelial to mesenchymal transition, migrate into the optical axis and produce opaque scar tissue. Despite preventive strategies such as modern cataract surgery and improved materials and shapes of intraocular lenses (IOLs), recent data suggests that about 28% of adults develop PCO at 5 years whereas 40% pediatric patients develop PCO by 2 years post cataract surgery (PCS). The only FDA approved treatment for PCO is YAG laser capsulotomy which is not devoid of side effects. Besides, YAG laser can be unsuitable for pediatric patients, while the availability of YAG lasers and technical expertise are limited in developing and underdeveloped countries, suggesting that understanding the molecular mechanisms of PCO to develop preventive therapeutics would improve the outcome of cataract surgery. Although it is well established that activated transforming growth factor-beta (TGFβ) signaling mediates fibrotic PCO, the initiation, activation, and bioavailability mechanisms of TGFβ signaling PCS are not well understood. Besides, if a preventive therapeutic against PCO is made available, at the start of my study, it was unclear whether clinicians treating cataract surgery patients would be interested in instituting it into their clinical practice. In total, four studies are covered here. The first one is a survey-based study on understating cataract surgeons’ viewpoints on the clinical challenges they encounter in routine practice and the types of therapeutic interventions that would enhance the long-term efficacy of cataract surgery and PCO (Chapter 3). The surgeons surveyed agree that PCO/VAO ( visual axis pacification) remains an unsolved problem in pediatric and veterinary cataract surgery while the long-term outcome of adult cataract surgery could be improved by additional attention to this issue. The next three studies are focused on understanding the molecular mechanisms of TGFβ signaling (the major mediator of PCO) regulation PCS. Chapter 4 focuses on understanding the ability of remnant LCs to express inflammatory cytokines leading to the infiltration of neutrophils and macrophages into the lens capsular bag, and the possible implications of these events in the initiation of TGFβ signaling PCS. Chapter 5 focuses on identifying an αV integrin heterodimer that is critical for the activation of TGFβ signaling PCS and characterizes the effects of an antibody which can block integrin function PCS. Chapter 6 focuses on elucidating the regulatory role of a fibrotic extracellular matrix (ECM) molecule, fibronectin, in relationship to latent TGFβ complex regulation PCS and its multifunctional roles in sustaining fibrotic PCO. All these studies fill the major knowledge gap, providing the regulatory mechanisms of initiation, activation, and the bioavailability of TGFβ signaling in PCO pathogenesis as well as novel molecular targets for PCO prevention.CataractsFibronectinIntegrinsPosterior Capsular OpacificationTGF beta signalingTherapeutic agentsThesis1241168149https://doi.org/10.58088/yph1-we422020-10-13en