| Center |
 Columbia University
|
| Award Year | 2014 |
| Pilot Study | Stem Cell-Based Model for HNF1A Deficiency in Human Pancreatic Beta Cells |
| Awardee | Haiqing Hua PhD |
| Abstract |
Recent progress in somatic cell reprogramming has enabled the generation of patient-specific induced pluripotent stem cells (iPSCs), including stem cells from diabetic subjects. However, whether iPSC-derived beta cells faithfully recapitulate pathologic phenotypes of human subjects, and can be used to test strategies/drugs to restore normal beta cell function, is not yet entirely clear. As proof-of-principle, we have modeled monogenic forms of diabetes, including Maturity-onset diabetes of the young (MODY). MODY accounts for 1 to 5 percent of all instances of diabetes in the United States and is caused by single gene mutations, resulting in defects in the development, proliferation/regeneration, and/or function of beta cells. MODY2 and MODY3, caused by mutations in the glucokinase (GCK) gene and HNF1A gene, respectively, account jointly for more than 80% of all MODY cases. In a previous study we demonstrated that the mature MODY2 beta cells derived from patients’ stem cells showed the anticipated reduced sensitivity of insulin (c-peptide) release to glucose. Importantly, correction of specific mutant base pair in the GCK locus by homologous recombination eliminated the functional defects in beta cell function in vivo. Utilizing this stem cell-based model system, we aim to identify the molecular mechanisms underlying the reduced function of HNF1A in beta cells. Haploinsufficiency of HNF1A, HNF4A and HNF1B cause diabetes (more clinically severe than GCK haploinsufficiency) but the exact mechanisms have not been fully elucidated. Insight into the roles of these transcription factors in the formation, survival and function of beta cells could advance strategies for prevention and mitigation of more prevalent forms of diabetes. Unlike humans, mice lacking one allele of HNF1A gene showed no diabetic phenotype, clearly indicating species differences regarding genotype-phenotype relationship, and pointing to the importance of using human cells for these studies. We have generated pluripotent stem cells from four MODY3 patients and differentiated these cells into insulin-producing beta cells. By applying the following approaches, we aim to understand the function of HNF1A in beta cell: |