Thursday, November 21, 2024
11/21/2024
Abstract This proposal seeks to elucidate the mechanisms of β-cell senescence, an aging hallmark, as a contributor to type 2 diabetes (T2D) and identify optimal therapeutic targets. Pancreatic insulin secreting β-cells, crucial to glucose homeostasis, are heavily secretory cells, equipped to respond to small changes in blood glucose levels and highly susceptible to stress by nutrient overload. My work has identified that mouse and human β- cells undergo senescence in response to insulin resistance (IR), leading to loss of cellular identity, impaired function and secretion of a unique senescence-associated secretory phenotype (SASP). Additionally, I showed that senolysis improved blood glucose levels and recovery of β-cell function and identity. I hypothesize that cellular senescence and its SASP are targetable drivers of β-cell dysfunction and loss. My goals are to understand the mechanisms behind β-cell senescence and identify the optimal therapeutic strategy. Aim 1. Identify the cell autonomous driver(s) of β-cell senescence and its functional effects. Based on our models of IR and DNA damage, we hypothesize that cyclin-dependent kinase inhibitor p21Cip1 is upregulated early in β-cell senescence and is followed by p16Ink4a. Genetic gain- and loss-of-function strategies will be used to compare the effects of p21Cpi1 and p16Ink4a on mouse and human β-cell function, identity and SASP. Additionally, the functional changes of senescent cells will be pinpointed. This aim will define the cell autonomous molecular mechanism(s) that drive β-cell senescence and its functional consequences. Aim 2. Elucidate the non-cell autonomous effects of the β-cell SASP. The hypothesis is that β-cell senescence can be driven by a non-cell autonomous mechanism through SASP factors, capable of impairing the function and gene identity of neighboring cells and precipitating their entry into senescence. To evaluate the effects of SASP upon neighboring β-cells, we will test the effects of the overall and specific selected factors on insulin secretion, senescence status and gene expression. Additionally, we will test the temporo-spatial effects of SASP on neighboring cells using our p21Cip1-dTomato Red MIP:GFP reporter mice. This aim will test the effects of β-cell SASP on non-senescent cells. Aim 3. Compare the effects of senolytic and senomorphic drugs in the recovery of β-cell function and identity. In our previous studies, senolysis effectively restored β-cell function and identity but a decrease in the number of senescent cells (senolysis) may be detrimental to an already inadequate beta cell mass, so perhaps only inhibiting their SASP (senomorphic effect) would render similar beneficial results. The hypothesis is that senormorphic drugs will restore β-cell function and identity without impacting cell mass. This aim will compare the effects of senolytic and senomorphic drugs on islets of human donors that have one or more of the following characteristics impairing glucose metabolism: older age, IR and T2D. This aim seeks to identify the optimal pharmacological mechanisms to recover the function and cellular identity without mass impairment.
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