Autoimmune-mediated destruction of ?-cells is the predominant cause of Type 1 diabetes mellitus (T1 DM). Current therapy, based on the replacement of ?-cells through islet transplantation and subsequent immune suppression, has significant limitations. In this proposal we focus on the natural ability of ?-cells to regenerate and restore glucose homeostasis in a mouse model of diabetes. The long-term goal of this project is to utilize the natural ability of ?-cells to regenerate as an innovative approach for the treatment of T1DM. This project represents a continuation of collaborative studies between the Chong, Philipson and Fu laboratories. Little is known about the capacity of regenerated islets to reproduce the normal physiological function of ?-cells and maintain glucose homeostasis after the development of overt diabetes. We have developed a new model of islet regeneration that will enable us to systematically define key mechanisms in ?-cell restoration. Our preliminary experiments demonstrate restoration of functional ?-cell mass and blood glucose regulation following an induced destruction of adult mouse ?-cells with high-dose streptozotocin (STZ). We also observed a significant requirement for splenocytes in islet cell regeneration after high-dose STZ treatment. ? ? The cellular and molecular basis for how splenocytes enhance ?-cell regeneration is not known. Published results have suggested that the signals triggering liver regeneration also trigger ?-cell proliferation and regeneration. Recent studies by Fu laboratory have revealed a novel role of T lymphocytes and lymphotoxin-? (LT?) signaling in facilitating liver regeneration. In this proposal, we will test the overall hypothesis that the cellular and soluble or cell membrane factors stimulating liver regeneration also stimulate ?-cell regeneration.
The Specific Aims are to:
Specific Aim 1. Test the hypothesis that T lymphocytes are the critical cell subset in the spleen regulating the regeneration of ? ?-cells in vivo. We will compare the rate of ?-cell regeneration in C57BL/6 mice lacking T cells, and made diabetic with STZ. We will also test whether splenocytes depleted of T cells have reduced efficacy in stimulating ?-cell regeneration in splenectomized, diabetic mice.
Specific Aim 2. Test the hypothesis that lymphotoxin-beta receptor (LT?R) signaling plays a critical role in stimulating ?-cell regeneration in vivo. We will test whether the rate of ?-cell regeneration is reduced when signaling through the LT?R is prevented by soluble LT?R (sLT?R) or in LT?R deficient mice. We will also test whether expression of the ligands of LT?R, LTa? or LIGHT, on spleen cells and LT?R on islet ?-cells is critical for stimulating ?-cell regeneration. ? ?
