MULTI-PARAMETRIC CHARACTERIZATION OF HUMAN ISLETS: PREDICTOR OF ISLET QUALITY, P

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. DESCRIPTION (provided by applicant): Islet transplantation has emerged as a promising option for restoring normal blood sugar control in people with Type 1 diabetes. However, key biological and institutional roadblocks hamper widespread utilization of this therapeutic strategy. Primary among these is the inability to recover a sufficient number of high quality islets, which is highly dependent pancreas preservation. Second, the absence of rapid, accurate, and sensitive pre-transplant test(s) that correlate with post-transplant function (i.e. potency assays) limits our ability to distinguish "healthy" preparations from those that will function poorly. Furthermore, high materials and equipment costs, the need for highly trained personnel and compulsory compliance with cGMP regulations makes islet isolation a difficult technology to consistently reproduce in every transplant program. For these reasons, methods should be developed that improve the ability to predict whether an islet preparation has the ability to function in the recipient after transplantation, and networks of regionalized islet isolation centers should be developed to minimize cold ischemic time and reduce institutional and financial hurdles. A successful Islet Transplant Program and isolation team has been established at the University of Wisconsin-Madison. The main goal of this application is to implement a series of quantitative measures of islet viability and functional potency in a regionalized pancreas recovery and islet distribution network and validate the ability of these parameters to predict islet graft function in patients. The proposal's specific aims are: 1) To distribute superior quality human islets for transplantation and research to members of a local islet research and transplant consortium and the ICR network based on a multi-parametric characterization of predictors of quality, potency and function. 2) To improve the quality of islet preparations by taking a three-pronged approach to sequentially optimize pancreas preservation, islet isolation, and post-isolation culture. Using the sensitive assessment tools, we will first test the effect of a novel trophic factor based preservation solution. We will also develop methods to minimize damage of islets during isolation, culture, and transportation focusing focusing on the reduction of ROS formation and the recovery of a "normal" metabolic state through supplementation of anti-oxidants to the isolation and culture media and optimization of culture pH, oxygen tension, and temperature. With this quality improvement program in place, we are confident we can provide over 20 million high quality islets over a five year period to ICR investigators and facilitate the development of additional islet transplantation programs to serve the diabetes community.