Basic Science Research
Our Basic Science Research has focused on the following areas:
1. Diagnosis of beta cell potency.
Our initial focus has been to create a sensitive and specific expanded panel of assessments that provide a level of sensitivity and objectivity beyond the current FDA standard measures of islet identity, purity, viability, sterility, and functional potency.
The purpose of this panel of tests, which we have named UW Extended Quality Control Assessment Program is:
- To qualify islets prior to transplantation in order to minimize or completely eliminate primary non-function or early dysfunction.
- To precisely determine the salutary effect of “in vitro” mechanical or pharmacological interventions to promote islet health and functional potency.
- To create a platform to mechanistically understand the biological effect on beta cells of new immunosuppressive drugs.
- To evaluate the biological potency of newly proliferated beta cells.
- To evaluate new methods of islet culture and transportation to remote islet transplantation facilities.
2. Creation of a gene expression profile as a potential fast readout that can predict and differentiate potent islets versus those that are not suitable for transplantation or research.
3. To evaluate alternative donor sources for islet transplantation. Optimization of Donation after Cardiac Death as potential donors for beta cell therapy.
Typically, organs are recovered from brain dead donors; however, limited experience shows donors who have not had brain death declaration, but family members consent after cardiac arrest, can donate organs that have successful post-transplant function. Therefore, this group of donors, termed Donation after Cardiac Death (DCD), might provide an additional pool of pancreata from which transplantable islets might be recovered. Our laboratory is interested in evaluating strategies that lead us to widely utilize this type of donor.
4. To evaluate donor treatment strategies to improve the quality of islets from donation after brain death.
At present, the majority of organs for transplant are recovered from donors after brain death (DBD). Organ deterioration following brain death is linked to multiple interrelated events, including the effect of massive acute cerebral injury, hypotension, and circulating factors such as catecholamines, hormones, coagulation factors, c-reactive protein, complement components and pro-inflammatory cytokines (PIC, e.g., IL-1b, TNFa, IFNg, IL-6). The profound pathophysiological damage linked to the inflammation/stress activation associated with brain death is of such magnitude that, in spite of conventional cardiopulmonary support, as many as 25% of potential donors are unsuitable for transplantation. Increased levels of PIC are responsible for some of the endocrine, acute-phase reactant, and organ abnormalities.
The goal is to create therapeutic interventions that eliminate the inflammation/stress activation associated with brain death which affect the pancreata utilized to recover islets for the purpose of islet transplantation and research, and also to improve the quality of other transplantable solid organs such as liver, kidney, heart and lung.
5. To evaluate strategies to maintain and improve islet quality.
Areas that are currently being explored in our laboratory:
- Minimization of hypoxia and inflammation at the time of islet isolation and islet culture
- Creation of an ideal environment that promotes beta cell proliferation and reduces immunogenicity
- Interaction of islets to endothelial cells and macrophages to maximize islet engraftment