Islet transplantation offers a potential treatment for type 1 diabetes (T1D) that could normalize blood glucose levels and circumvent the development of diabetes-associated complications. Despite recent advances in islet isolation and immunosuppressive regimens, many islet recipients gradually lose islet function after transplantation. Because islets can up-regulate their production of insulin, measurements of blood glucose, insulin C-peptide production and 1st phase insulin release detect the loss of islet function only after a significant number of islets have already been lost. It has long been hoped that transplanted islets could be directly imaged, so that their survival could be longitudinally monitored in recipients, allowing clinicians to tailor therapies to more effectively support islet survival post-transplantation. The noninvasive imaging of transplanted islets in humans now appears to be feasible, and awaits translation from rodents to nonhuman primates, and then to humans. In this R21 proposal we will test the hypotheses that; 1) the viral delivery of reporter genes, followed by optical and micro-positron emission tomography (microPET) imaging, provide new modalities to noninvasively monitor islet cell mass after intraportal islet transplantation in rodents and; 2) optical and microPET imaging can detect islet rejection earlier than measurements of blood glucose and C-peptide levels. We will also evaluate whether viral infection and long-term PET reporter expression and PET imaging is deleterious to the islet graft. If this project is successful, a subsequent R33 application will attempt to extend this technology to the imaging of transplanted islets in the liver of non-human primates. Thus, the results of this proposal may provide a foundation that will lead to new tools for improving the care and treatment of those with type 1 diabetes.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21DK069839-02
Application #
6954643
Study Section
Special Emphasis Panel (ZDK1-GRB-6 (O1))
Program Officer
Laughlin, Maren R
Project Start
2004-09-30
Project End
2007-08-31
Budget Start
2005-09-01
Budget End
2007-08-31
Support Year
2
Fiscal Year
2005
Total Cost
$382,941
Indirect Cost
Name
University of California Los Angeles
Department
Pharmacology
Type
Schools of Medicine
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
Washburn, L R; Dang, H; Tian, J et al. (2007) The postnatal maternal environment influences diabetes development in nonobese diabetic mice. J Autoimmun 28:19-23
Lu, Yuxin; Dang, Hoa; Middleton, Blake et al. (2006) Long-term monitoring of transplanted islets using positron emission tomography. Mol Ther 14:851-6
Lu, Yuxin; Dang, Hoa; Middleton, Blake et al. (2006) Noninvasive imaging of islet grafts using positron-emission tomography. Proc Natl Acad Sci U S A 103:11294-9
Lu, Yuxin; Dang, Hoa; Middleton, Blake et al. (2004) Bioluminescent monitoring of islet graft survival after transplantation. Mol Ther 9:428-35