Project Details

Description

Patients of both major forms of diabetes suffer from inadequate beta cell mass and would benefit from therapies that increase the number or function of beta cells. The breakdown of glucose itself is a signal that makes beta cells grow. Dr. Scott found that a glucose-sensing protein, a transcription factor (proteins that turn on genes) called carbohydrate response element binding protein (ChREBPa), is required for glucose-stimulated beta cell proliferation. Furthermore, Dr. Scott found that increasing ChREBPa in beta cells amplifies glucose-stimulated beta cell growth. In the present proposal, Dr. Scott shows that ChREBPa increases the size and activity of mitochondria, which increases the ability of cells to grow. In addition, Dr. Scott shows that this effect is mediated by activation of Nrf2, an antioxidant transcription factor. Dr. Scott will test the therapeutic potential of activating in human beta cells. Dr. Scott hypothesizes that ChREBPa redirects beta cell metabolism by activating the Nrf2 to increase mitochondrial activity, which promotes beta cell proliferation while providing antioxidant protection. Specific Aims are to: 1) Determine if Nrf2 activation is sufficient to mimic the ChREBPa-mediated amplification of glucose-stimulated beta cell proliferation, by increasing Nrf2 levels in human and rodent beta cells, and 2) Determine if Nrf2 activation in human islets improves islet transplantation outcomes, in models of human islet transplantation into SCID mice. Completion of these Aims will test the exciting and innovative hypothesis that activation of Nrf2 will lead to an important therapeutic option for the expansion of beta cell mass.
StatusFinished
Effective start/end date1/01/1731/12/19

Funding

  • American Diabetes Association

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