β cell dysfunction during aging: Studies on the role of p21 in the regulation of the Unfolded Protein Response

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The progressive loss of certain cell populations that compromises tissue and organ function represents a common feature of age-associated diseases such as diabetes. Endoplasmic reticulum (ER) stress has been associated to this progressive cell loss of β cells in diabetes that occurs during aging. ER stress is induced when various intrinsic or extrinsic factors cause the accumulation of misfolded and unfolded proteins in the ER generating conditions that are unfavorable for the cells’ survival and function. Resolution of ER stress is attained by the initiation of a prosurvival adaptive biochemical cascade, designated as the unfolded protein response (UPR), which aims to restore tissue homeostasis. When however ER stress is prolonged or severe, pro-apoptotic signals associated with the UPR predominate eliminating the damaged cells and compromising tissue and organ function which prevails during aging. In type 2 diabetes in particular, UPR progressively causes beta cell apoptosis and ultimately, pancreatic dysfunction contributing to the pathogenesis of age- associated diabetes. It is conceivable that the identification of modulators for the UPR, and particularly those capable of re- enforcing its pro-survival as opposed to its pro-apoptotic activity, may be of particular benefit in aging- associated conditions. Our laboratory discovered that the cell cycle regulator p21 represents such a modulator that is capable of inhibiting the pro-apoptotic activity of the UPR. In the present study we propose to evaluate the induction of ER stress, and the regulatory role of p21 in relation to aging. By using pancreatic islets isolated from young and old mice as a model we will assess how UPR is induced in relation to age and how it affects islets’ function and survival. For our studies islets from wild type, p21-deficient, p53-deficient and CHOP- deficient mice will be used. Our specific aims are: 1. To monitor the profile of p21 expression and UPR induction in islets in response to ER stress at different ages. 2. To explore if pharmacological and genetic modulation of p21 expression affects the survival and function of pancreatic islets in association with age during ER stress. Both male and female mice will be included in our analyses since gender-specific differences may be linked to distinct UPR-related responses. It is conceivable that our findings will illuminate the operation of a biologically important and clinically relevant link between p21, ER stress and aging and may find application in the management of age-associated diabetes.