The lens is a metabolically active tissue which demonstrates continued growth throughout life. Insulin (INS) and insulin-like growth factor I (IGF-I) play a major role in lens growth and development. The initial step in cellular regulation by these hormones is their binding to the (x subunit of specific transmembrane receptors. This hormone-receptor interaction stimulates the tyrosine kinase activity (TKA) of the receptors' beta subunit, initiating a signal transduction pathway. A decrease in the INS receptor TKA has been associated with metabolic alterations, such as those observed in the insulin resistance of aging. Unfortunately, knowledge of INS and IGF-I receptor interaction(s) with their associated signal transduction mechanism(s) is limited in the lens. Thus, we do not know if alteration of the lens INS and IGF-I receptor TKA plays a role in the morphologic changes such as cataract formation, frequently associated with the aging lens. The studies in this proposal are designed to examine this issue in detail by studying INS and IGF-I interactions with their individual receptors and the recently designated INS/IGF-I """"""""hybrid"""""""" receptors. These hybrid receptors may play an important role in helping the lens to maintain normal cell function by allowing IGF-I to act as an INS agonist whenever necessary. Upon completion of the proposed studies (which examine freshly isolated and cultured chicken, bovine, and normal human lens cells), we will have determined: a) the specific binding parameters of INS and .IGF-l for their respective receptors, including receptor cross-reactivity and identification of """"""""hybrid receptors""""""""; b) the structure and molecular size of the receptors for these two hormones; c) the effect of """"""""hormone- activated"""""""" receptors on the phosphorylation of lens cell proteins; d) the types, location, and number of glucose transport proteins in lens cells; e) the action of INS and/or IGF-I on the message, expression, and movement of the glucose transport protein(s); f) the effect of INS and/or IGF-I on protein synthesis in lens cells; and g) the effect of aging on- the afore mentioned activities including: the INS and IGF-I receptor and its associated signal transduction, lens cell glucose transporters and INS and/or IGF-I stimulated protein synthesis. Our long term objectives include expanding these studies to examine in lens cells the relationship between hormone-receptor interactions with their associated signal transduction pathway(s), and their metabolic end points, in other states of insulin resistance, such as diabetes, obesity and hypertension. These studies will enhance our understanding of hormone-receptor interactions in the lens and contribute to our understand in of lens pathology.
