BM SUBPOPULATIONS TO REPAIR HUMAN ISLET INJURY AND SUPPORT ITS LONGEVITY

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. There has been no change in the scope of this project. The success of islet transplantation is hampered by the high rate of islet cell death and dysfunction after isolation. Therefore, the repair of islet damage from the isolation process and the opportunity to maintain islets long term in vitro as a new islet resource would represent significant advances and lead to a more widespread use of islet cell transplantation. Successful utilization of bone marrow in repairing skin, neuron, heart, and muscle injury led us to propose that bone marrow could offer a potential solution to these challenges. In our preliminary studies using co-cultures of whole bone marrow with islet, bone marrow was shown to increase islet function/survival (more than six months), stimulate islet growth and generate long-term insulin producing tissue in vitro. We hypothesize that specific subpopulations of marrow cells may be responsible for these findings. We have also hypothesized that extracellular ATP, ATP receptor (purinoreceptor P2XR), and interleukin 1beta (IL-1beta) are involved in bone marrow-induced repair of islet injury. In this project, we plan to identify whether multiple or single specific lineage marrow cells contribute to islet reconstitution. We will examine whether these reconstituted islets have sufficient function and vascularization in vivo as determined by transplantation into NOD/SCID mice. Finally, we will investigate whether bone marrow modulates ATP, its receptor P2XR, IL-1¿ and its downstream pathways. This project will have benefits for current islet transplantation protocols and will provide insight into the mechanisms of islet cell death and regeneration.