Mice to Men
YongKyung Kim, Ph.D.
University of Colorado Anschutz Medical Campus Barbara Davis Center for Diabetes
I am in the process of weaning pups from PTPN2 βKO mice breeding cages. I have several cohorts of controls, PTPN2 βhet, and PTPN2 βKO male mice and I will be measuring the oxygen consumption rate and extra cellular acidification rate of these mice at 9 weeks-of-age (estimate date is 7th Nov 2019). Also, to prepare for the large number of mice I will need for my pro-inflammatory cytokine treatment experiment, I have set up 10 breeding cages and am awaiting for the birth of the pups.
Type 1 diabetes (T1D) results in the irreversible destruction of insulin-producing beta cells by an individual’s own immune system. Most treatments to date have focused on ways to block the erroneous immune response, but have not resulted in long term protection or reversal of diabetes. Mice-to-Men proposes an alternative approach to treatment by understanding how the beta cells themselves contribute to disease, and to identify methods to protect their destruction from the immune system. Experiments with mice have provided a good model system with encouraging results. Mice-to-Men will assess the benefits of this beta cell protection system to humans.
We have focused our studies on a protein called Protein tyrosine phosphatase N2 (PTPN2) that was identified as a T1D risk gene in patients with T1D. PTPN2 is found in both the immune cells and beta cells, and we hypothesize that individuals with mutations in PTPN2 have disrupted beta cell function and/or increased susceptibility to cell death that contributes to their destruction.
To parse out the contribution of beta cell dysfunction to T1D, we have created a mouse model that removes PTPN2 just from the insulin-producing beta cells. In the study supported by DRC, we will subject these mutant mice to an autoimmune environment and assess how the beta cells respond in comparison to beta cells with intact PTPN2. Based on our preliminary experiments, we believe the mutant beta cells have specific cellular defects that compromise their survival and function. We will characterize these defects to establish whether their correction or amelioration can protect the beta cells from destruction by the immune system.
The mouse experiments provide a good model system to study the beta cell function of PTPN2 in a physiologically relevant setting of T1D. However, since there are differences between mice and humans, we have also collected blood cells from T1D individuals with mutations in PTPN2. We will use these cells to generate mutant pluripotent stem cells that can then be differentiated in to insulin producing beta-like cells. These cells can then be subjected to autoimmune-mimicking conditions to determine whether human PTPN2 mutant beta cells have similar defects observed in the mouse system. The modified cells can also be used to test candidate treatments/drugs that could potentially be used to protect the beta cell from the immune system.
The overall goal of this study is to identify how beta cells contribute to their own demise in T1D and to develop ways of protecting the beta cell in the face of assault from the immune system.