MODEL OF ISLET REGENERATION AND NEOGENESIS

Insulin dependent diabetes mellitus (IDDM) is caused by a paucity of
insulin-producing cells in the islets of Langerhans. In virtually all
circumstances the islet cells have no regenerative capacity after birth
and once they are destroyed by inflammatory cells no recovery is
possible. In this proposal we will study the mechanism by which the
insulin-producing beta cells are regenerated with the eventual goal of
identifying specific factors that are critically involved in their
development. For these studies we will utilize a strain of transgenic
mice that has demonstrated a dramatically high level of pancreatic duct
cell proliferation and neogenesis of islet cells during adult life. The
experimental studies proposed in this application will distinguish
between two potential models accounting for the observed regeneration.
We will determine what potentially inductive molecules are present in the
regenerating pancreas. The identity of cells required for the
proliferation/differentiation will be established by perturbing the
system genetically and through the use of mechanisms that allow the
depletion of specific cell categories in the regenerating pancreas.
Lastly, we will utilize an in vitro system to integrate the data
collected from the studies on the transgenic mice. Cultures of
pancreatic duct epithelial cells will be derived from both transgenic and
non-transgenic animals. These duct cells cultures will be studied
histologically and also for their ability to differentiate in vitro and
in vivo. Lastly, we will design specific strategies, based upon the
information gained in the proposed studies to induce islet cell
differentiation in vitro. The proposed studies will augment the
potential of inducing islet cell growth and regrowth as a means of
replenishing the insulin producing machinery lost in IDDM.