Grant Number: 5K08CA105064-02
PI: Hirofumi Noguchi, MD, PhD
Funding Organization: Juvenile Diabetes Research Foundation
Project Start: March 1, 2008
Project End: February 28, 2009
Abstract:
During the islet isolation process and subsequent clinical transplantation, islets are subjected to severe adverse conditions that impair survival and ultimately contribute to graft failure. Although pancreas preservation using the two-layer method (TLM) has improved transplant results by protecting isolated islets against apoptosis through the mitochondrial pathway, it cannot prevent activation of c-Jun NH2-terminal kinase (JNK) in isolated islets. This study investigates how JNK is activate during islet isolation and whether pancreas preservation with a JNK inhibitor can prevent apoptosis of islet cells immediately after isolation.
Initially, porcine pancreata are preserved with or without 10μM of a JNK inhibitor. Islet isolation from pig pancreata is conducted in accordance with the method described in the Edmonton protocol. Activity of JNK is mapped during the isolation procedure. JNK activity is measured using the KinaseSTAR JNK Activity Assay Kit. To determine whether preservation with the JNK inhibitor enhances islet graft function in vivo, islets are incubated for 1 day and then transplanted below the kidney capsule of STZ-induced diabetic SCID mice. Pancreas preservation with a JNK inhibitor prevents islet apoptosis during isolation and transplantation using porcine pancreta. We will compare this preservation solution including the JNK inhibitor with the standard solution using research grade human pancreata.
Currently, two or three islet transplantations are standard for achieving insulin-independent status. If we are able to improve the efficacy of islet isolation and transplantation using preservation solution with JNK inhibitor, the majority of islet transplantations might be performed with a single infusion to achieve insulin-independence.
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