Despite more than a decade of work in human islet cell transplantation, successes have been limited. The current paradigm of islet graft failure involves immune mediated rejection. However, the islet is a complex 3-dimensional structure; and the endocrine function of the islet is likely determined by the structure. Nonetheless, surprisingly little is known about how islet structure is created and maintained. The hypothesis of the work is that adult islet grafts fail after transplantation by disruption of the normal 3-dimensional architecture. In fetal islet transplants this loss of integrity causes developmental failure. The hypothesis is supported by other cellular systems in which cellular matrix can promote epithelial cell growth and differentiation, while the loss of matrix has been implicated in epithelial cell death by apoptosis. However, nothing is known about matrix structure and function in human islets in normal pancreas or after transplantation. Preliminary data shows the expression of integrin adhesion molecules in human islets and matrix ligands for these receptors as a component of islet structure.
The specific aims are: 1) To demonstrate that integrin adhesion molecules and extracellular matrix determine the structure of normal human islets and that this is a critical determinant of islet function. The applicants will use confocal and electronmicroscopy studies comparing adult and fetal islets and establish the correlations between integrin function and islet structure using purified adult and fetal cell preparations to compare the use of adhesion molecules in islet cell growth, cell spreading, and migration on defined matrix components. 2) To demonstrate the role of integrins in matrix and fetal and adult islet function after transplantation in the NOD/SCID, demonstrate that transplantation to an unfavorable site results in a disruption of islet structure and function, and demonstrate that using 3-dimensional mesh cultures of islet cells can protect islet structure and function as a strategy for clinical transplantation. 3) To validate the functional importance of maintaining islet adhesion and matrix structure in successful transplantation, the applicants will use mAbs and novel peptide analogs to specifically block the function of different adhesion molecules after transplantation.
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