This R21 application aims at exploring the feasibility of a novel approach to address the Program announcement area of interest on the development of cell therapies to treat diabetes. Pancreatic islet transplantation is becoming an alternative to insulin therapy in patients suffering from the most severe forms of Type 1 diabetes. However, a major obstacle to success of islet transplantation is early graft loss mediated by apoptosis and necrosis induced by the instant blood-mediated inflammatory reaction (IBMIR), occurring after transplantation of islets into liver. IBMR is a clotting reaction characterized by rapid platelet deposition on islet surface, activation of the coagulation and complement cascades, and leukocyte infiltration of the islets. A critical molecule causing IBMR is tissue factor (TF), a natural mediator of coagulation. TF is known to be present in isolated islets and its expression is tightly associated with islet graft failure. The basic idea is to engineer a molecule that could efficiently prevent the production of TF in islets. We propose to develop a chimeric molecule composed of two domains: a protein transduction domain (PTD), to warrant molecule distribution throughout the whole islets and a specific anti-gene peptide nucleic acid (PNA) component that will block transcription of TF gene. To develop this project we will synthesize and characterize TAT-PNA molecules at the molecular level and will test their efficiency to inhibit IBMIR using a relevant in vivo model of islet transplantation. The development of such a novel PTD-antiTF PNA reagent, may allow the in vitro treatment of islets preceding transplantation in order to obliterate the IBMR toxic effects and thus increasing the successful outcome of transplantation. Such approach could minimize necessity for multiple transplants thus reducing the problem due to the shortage of cadaveric donor pancreata available for islet transplantation. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21DK076098-01
Application #
7137187
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Program Officer
Appel, Michael C
Project Start
2006-08-15
Project End
2008-07-31
Budget Start
2006-08-15
Budget End
2007-07-31
Support Year
1
Fiscal Year
2006
Total Cost
$152,584
Indirect Cost
Name
University of Miami School of Medicine
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
052780918
City
Miami
State
FL
Country
United States
Zip Code
33146
Fotino, Nicoletta; Fotino, Carmen; Pileggi, Antonello (2015) Re-engineering islet cell transplantation. Pharmacol Res 98:76-85
Pileggi, Antonello; Ricordi, Camillo (2013) A new home for pancreatic islet transplants: the bone marrow. Diabetes 62:3333-5
Pileggi, Antonello; Xu, Xiumin; Tan, Jianming et al. (2013) Mesenchymal stromal (stem) cells to improve solid organ transplant outcome: lessons from the initial clinical trials. Curr Opin Organ Transplant 18:672-81
Pileggi, Antonello (2012) Mesenchymal stem cells for the treatment of diabetes. Diabetes 61:1355-6
Fotino, Carmen; Ricordi, Camillo; Lauriola, Vincenzo et al. (2010) Bone marrow-derived stem cell transplantation for the treatment of insulin-dependent diabetes. Rev Diabet Stud 7:144-57