In honor of Matt Polakow, the Tarson Family funded this project in its entirety.

PROJECT DESCRIPTION

Type 1 Diabetes (T1D) is a chronic disorder in which patients actively lose the insulin-secreting beta cells in the pancreatic islets. Despite extensive research to cure T1D that ranges from insulin treatment to transplanting healthy beta cells, there is no unified hypothesis for the mechanisms that initiate and sustain the loss of beta cells.
Recent research from our lab clearly shows the role of dying beta cells (senescence) in the progression of T1D. Preliminary data also suggests certain substances can increase the production of compensating chemicals to substantially reduce the death of beta cells. These agents also helped in reversing the progression of T1D in mice.

Two major issues arise from these findings: 1) what triggers the death of beta cells in the pancreas of T1D mice, and 2) how to translate this information to humans.

Current work from our lab strongly suggests that a deficient DNA repair machinery results in the accumulation of structured problems in mice beta cells, Double Strand Breaks (DSB), that causes beta-cell death. We propose to develop a unique humanized mouse model that will allow us to test the clearance of these dying human beta cells using a unique humanized mouse model.

Research Project and Approach

To test the above hypothesis, our specific objectives in the proposed study are:

1) Determine how beta cells die as a result of DSB which may be the cause of deficient DNA repair machinery; and

2) Use a humanized mouse model to test the targeted clearance of senescent human beta cells in vivo.

The answers to the above questions will not only provide substantial advancement in our understanding of T1D but may also support the development of a new approach for preventing, and possibly curing the disease. The exact triggers and precise mechanism which causes beta cells to die during the onset of T1D are still unclear. However, it is known that persistent DSB is capable of inducing beta cell death. Current work from our lab strongly suggests the presence of DSB in infiltrated islets of humanized T1D mice. Experimental data from other labs evidences that the deletion of an important enzyme of DSB machinery causes beta cells, in the humanized mouse, to completely resist chemically induced T1D. We will test this hypothesis by removing this enzyme to determine if this may prevent the onset and persistence of T1D.