Pancreatic endocrine cell differentitation and dedifferentiation, reprogramming of pancreatic acinar cells into new beta cells, genetic and epigenetic regulation of cellular plasticity
Our research has long been focused on the use of genetically-altered mice to advance our understanding of the biology of the pancreatic beta cell, which plays a central role in the pathophysiology of monogenic and polygenic glycemic disorders including type 1 and type 2 diabetes mellitus. We have developed novel and efficient methods for rapidly generating mice in which key genes that control cell fate decisions in pancreas development are tagged with different colored fluorescent proteins, conditionally knocked out, or placed under the control of exogenous chemical inducers. These animals have enabled world-wide advances in multiple facets of both pancreatic and beta cell biology.
Our current research is focused on understanding how genetic and epigenetic factors interact to maintain pancreatic cellular identities. This is important for two reasons. First, the loss of beta cell identity, and hence function, may be an important aspect of disease progression in type 2 diabetes mellitus. To study this we are utilizing mice that lack ATP-sensitive potassium channels and are chronically hyperstimulated independent of the blood glucose concentration. Second, the development of new cell-based therapies based on reprogramming strategies holds great promise for the treatment of type 1 diabetes mellitus. Thus, the ability to selectively disrupt acinar cell identity may be critical for the efficient reprogramming of acinar to beta cells by the forced expression of exogenous transcription factors.
In addition to our proven ability to derive state-of-the-art mouse models, we have begun to utilize advanced methodologies, such as RNA-seq and ChIP-seq, to characterize the effects of specific genetic and chemical manipulations on gene expression profile and epigenetic landscape of the cell. The management and analysis of this information has also led us to become interested in the use of both informatics and bioinformatics strategies in order to build models that describe both the gene regulatory networks and epigenetic architectures that determine and maintain specific pancreatic cellular identities.