The Mechanisms that Underlie Mammalian Pancreas Organogenesis and Pancreatic Diseases, Including Diabetes and Pancreatic Cancer

We are currently using multiple tools including transgenic mouse models in which gene expression is conditionally regulated to manipulate the activity of specific signaling pathways. The information gained from these studies is used to optimize and develop novel methods to generate functional insulin-producing β-cells from human stem cell populations such as human embryonic stem cells (hESCs) and induced pluripotentstem (iPS) cells.

beta cell function

Several avenues can be explored to replenish β-cell function in diabetic patients, ranging from generation of functional cells from stem cells (see below) to regenerating endogenous injured β-cells. To accomplish these goals, efforts need to be undertaken to understand the differentiation state and functional capacities of β-cell population within diabetic patients. To gain insights into β-cell function, we are currently using different models to study the role of specific signaling pathways in mouse and human β-cells (Landsman et al. PNAS 2011, Puri et al. Genes Dev 2013, Puri et al. PLoS One 2013).

In addition, we are interested in the mechanisms that regulate β-cell regeneration in the mouse, using a model where tamoxifen-mediated induction of c-myc expression leads to β-cell apoptosis followed by recovery (Cano et al. Diabetes 2008). This tool allows us to test the capacity of young and aged β-cell to regenerate and define modulators of this process.

the immune system in pancreas injury and regeneration

We are interested in understanding how different immune cells contribute to the process of pancreatic regeneration following injury. One of our goals has been to dissect the interactions between resident tissue cells and infiltrating immune cells during injury, and address how immunological factors can affect cellular plasticity (Folias et al. PLoS One 2014). This issue is particularly relevant for stem cell studies, as well as current transplantation and regenerative medicine therapies. Additionally, de-differentiated acinar cells harboring genetic mutations can develop into pancreatic cancer precursors, highlighting the importance in understanding the initiation event of this potentially carcinogenic cellular transformation.