Cirulli, Vincenzo , M.D.
Adhesive and migratory cues for islet cells
General Research Subject: Both Type 1 And Type 2 Diabetes
Focus: Immunology, Islet Biology\Beta Cell Growth and Differentiation, Transplantation
Type of Grant: Basic Science
Project Start Date: January 1, 2011
Project End Date: December 31, 2013
Netrins and Slits are proteins that have been discovered in the developing brain where they guide neural cell migrating through mechanisms of 'attraction' and 'repulsion'. Our laboratory has demonstrated that Netrin-1 mediates the adhesion and migration of pancreatic progenitors during development. More recently we have extended our studies to Slit-2, an antagonist of Netrins function that regulates a wide range of functions. For example it has been shown that Slit-2 can promote maturation of certain epithelial cells, repel lymphocytes, and attract endothelial cells forming blood vessels. Interestingly, we find that Slit-2 is selectively produced in human pancreatic islets where if supports pancreatic cell attachment. We also find that Slit-2 expression in pancreatic islets can be reduced by inflammatory cytokines produced by lymphocytes, suggesting a mechanism by which leukocytes may overcome the repellent function of Slit-2 produced by islets and infiltrate the islets during autoimmune inflammation.
In light of these observations, we propose to test whether Slit-2 regulates the maturation of pancreatic progenitors into islet cells (Aim 1), and promotes the formation of blood vessels necessary for both islet development during fetal life, and adult islet engraftment following transplantation, by mechanisms of attraction on endothelial cells (Aim 2). In the same experiments we will also test whether Slit-2 can prevent islet rejection by mechanisms of repulsion on unwanted lymphocytes (Aim 2). These studies may provide important insights on the function(s) of Slit-2 in pancreatic islets, and possibly help in the design of novel strategies to prevent islet transplant rejection.
What area of diabetes research does your project cover? What role will this particular project play in preventing, treating and/or curing diabetes?
This project focuses on mechanisms that drive the development of islet cells from a pool of putative progenitors. Specifically, experiments planned under this project will study the function of a neural protein named Slit-2 that we found to elicit the migration of Sox9+ pancreatic progenitors, and possibly their differentiation toward the islet cell lineage. Our goal in these studies is to fully characterize the function of Slit-2 and its receptors as motogenic cues that drive the recruitment of immature islet progenitors into a pool of differentiating islet cells.
We anticipate that understanding these mechanisms will help define optimal conditions that can be exploited to trigger the regeneration of islet cells from pool of Sox9+ pancreatic progenitors. Ultimately, results from these studies may have an impact on the design of novel strategies to induce islet cell regeneration in vivo, and/or help define novel strategies to cure diabetes by cell-based replacement therapies.
If a person with diabetes were to ask you how your project will help them in the future, how would you respond?
The primary goal of our studies is to uncover the function of a neural protein named Sli-2 that we found to be expressed in the developing pancreas, and that appears to function as a migratory cue for pancreatic ductal cells marked by the expression of the progenitor marker Sox9. Our hypothesis is that once Sli-2 is released in the extracellular environment and presented to Sox9+ progenitors it exerts 'awakening' functions on populations of 'dormant' islet progenitors postulated to be present even in an adult pancreas. So far, our limited understanding of islet regeneration suggests that for new beta cells to be formed it is important to recruit 'dormant' progenitors and 'instruct' them to mature toward an islet cell.
Ultimately, understanding these mechanisms will help define optimal conditions that can be exploited to trigger the regeneration of islet cells from pools of pancreatic progenitors. Thus, results from these studies may have an impact on the design of novel strategies to induce islet cell regeneration in vivo, and/or help define novel strategies to cure diabetes by cell-based replacement therapies.
Why is it important for you, personally, to become involved in diabetes research? What role will this award play in your research efforts?
Beside a personal commitment to diabetes research motivated by the fact that three members of my family have diabetes, throughout my career as an adult endocrinologist I have always regarded basic research as the best investment for improving future therapies for diabetics.
Presently, this ADA Basic Science Award research award will play a significant role in jump-starting a new direction for my research program. Thus, having recently moved my laboratory to the University of Washington at the Institute for Stem Cells and Regenerative Medicine, I anticipate that being able to implement the studies outlined in this new project will position my research efforts at a critically important interface between the developmental biology of islet cells and the biology of stem cells and regenerative medicine.
In what direction do you see the future of diabetes research going?
This is an exciting new era for diabetes research. Based on recent progress achieved in stem cell biology and regenerative medicine, I anticipate that in the next decade or so, we will witness a number of further accomplishments in stem cell biology that will lead to viable cell-based replacement strategies that will be amenable to a clinical setting. A positive sign in this direction is also provided by the rising interest of big pharmaceutical companies to invest in regenerative medicine and stem cell biology.
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