Mechanisms of diabetes and aging in constitutively active, phosphorylation-resistant pRb knockin mice
Description: The tumor suppressor pRb is regulated by cyclin-dependent kinases (CDKs) that phosphorylate and inactivate it, leading to uncontrolled cell division. Conversely, inhibition of pRb phosphorylation suppresses cell division. Over the years, many studies with cultured cells were used to define a model for pRb function, where this protein was thought to stop cells from transitioning between a so-called growth phase (G1) and the DNA duplication S-phase, but this model has never been tested in mice, and the consequences of blocking pRb phosphorylation on development and homeostasis are not known. We have directly tested this model in mice and found, to our great surprise, that blocking pRb phosphorylation (RbdeltaK7) leads to various signs of aging, including inhibition of pancreatic beta-cell regeneration, induction of senescence (permanent cell cycle exit) and diabetes. Strikingly, diabetes was attenuated by feeding RbdeltaK7 mice on vitamin C diet. We hypothesize that pancreatic islets of RbdeltaK7 mice provide a unique platform to study diabetes and cellular regeneration during aging. In this project, we will use RbdeltaK7 mice to define: i) the senescence and aging phenotypes of pancreatic RbdeltaK7 islets, ii) whether pancreatic beta-cells in RbdeltaK7 mice enter a repressive state that prevents cell cycle re-entry, and iii) whether specific elimination of senescent cells together with vitamin C can cure diabetes and extend lifespan of RbdeltaK7 mice and a mouse model of type 1 diabetes.
Amount: CA$799,400
Funding type: research
Funder scheme: Project Grant
Start date: 2021-10-01
End date: 2026-09-30
Investigator: Eldad Zacksenhaus
Institution: University Health Network (Toronto)
Subfield: Surgery
Field: Medicine
Domain: Health Sciences
Funded outputs count: 0
Funder award ID: 178033_1
OpenAlex ID: G5429640633