Understanding mechanisms of novel diabetes genes and risk variants using hiPS cells

The human genome contains a large number of genetic variants associated with disease risk, including for diabetes. However, for most variants, the functional consequence has not been demonstrated in human cells, and functional assays to evaluate the consequences in animal models are limited to conserved regions. The PI has collected a set of novel variants predicted to alter the function of proteins implicated in familial diabetes. She proposes to study variants in two genes TRIB3 and SEL1L for detailed characterization, because of their likely role in endoplasmic reticulum (ER) function. The ER is critical for proinsulin folding and insulin secretion from beta cells. There is increasing evidence that the presence of unfolded proteins is of central importance to the failure of beta cells in all forms of diabetes, including type 1 and type 2 diabetes. The PI will introduce mutations identified in patients into human pluripotent stem cells, and test their developmental and functional properties of iPS-derived beta cells in vitro as well as after grafting into mice in vivo. She has established an efficient experimental system for beta cell differentiation and grafting without the formation of teratomas that allows the functional study of human genotypes in a physiologically relevant environment. The proposed studies have the potential to identify two novel diabetes genes, and enable the study of mechanisms by which protein folding stress causes beta cells to fail. The proposed work is therefore relevant to all forms of diabetes.