Our Services

Projects

"Armor Plating" Islets Against Attack From the Immune System
Increasing the Supply of Islets

Improving Tolerance
Finding the Best Vectors
Preventing Nerve Damage

"Armor Plating" Islets Against Attack From the Immune System

Transplanting healthy islets into Type 1 diabetes patients poses a double challenge to scientists. First, they must find a way to overcome the pre-existing autoimmunity that Type 1 diabetes patients have. In Type 1 diabetes, the cells of a person's own immune system destroy the islets in the pancreas. These islet-cell killing immune cells can also destroy transplanted islet tissue. Researchers must also deal with "alloimmunity," the normal defenses against foreign tissues that the human body turns on whenever a transplant takes place, producing cells to kill the foreign intruder.

The project's goal is to give islets the ability to defend themselves from both autoimmunity and alloimmunity. To do so, the team will attempt to transfer protective genes to the islets before they are transplanted. The project will determine which genes do the best job of protection and which vectors do the best job of delivering the "armor plating" genes to the islets. The initial research will be on mice and larger animals, with human therapy as the ultimate goal.

Top

Increasing the Supply of Islets

Principal Investigator - James Pipas, PhD

Living human and rodent islets have been isolated and cultured in vitro, i.e., in test tubes and petri dishes. However, the in vitro cells don't live very long. In the past, researchers have tried to prolong these cells' life and increase their number by introducing the gene for a viral protein called T antigen. T antigen stimulates cell growth, but unfortunately this growth is uncontrolled, turning normal cells into tumor cells. Moreover, the islets expressing T antigen eventually lose their ability to produce insulin. The University of Pittsburgh researchers have produced a group of promising genetically altered T antigens. They will test whether these T antigen variants can grow more islets in vitro, while keeping growth under control and preserving the islets' insulin-producing capabilities. The goal of the project is to increase the supply of robust islets available for transplant.

Principal Investigator - Andrew Stewart, MD

Gene therapy researchers have identified and developed protein molecules called "growth factors" that-as the name implies-enables cells to grow. Unfortunately, these proteins are difficult to produce, are in limited supply and can have uneven effects. The University of Pittsburgh has developed a way to use an adenovirus, a modified cold virus, to deliver growth factor genes to islets in vitro. This could supply virtually unlimited amounts of growth factor to every islet cell. Dr. Stewart's project will examine the effect that genes for three of the most promising growth factors (parathyroid hormone-related protein, placental lactogen and hepatocyte growth factor), delivered via adenovirus, have on in vitro mouse, rat and human islets. The project will also explore how well the islets that receive the growth factors function once they are transplanted into diabetic rodents.

Top

Improving Tolerance

Principal Investigator - John Fung, MD, PhD

One of the challenges facing physicians attempting to transplant normal functioning islets into Type 1 diabetes patients is finding a way to overcome the normal defenses against foreign tissues that the human body turns on whenever a transplant takes place, also known as the alloimmune response. Dr. Fung and co-workers will explore whether the alloimmune response can be moderated by genetically altering dendritic cells, which originate in bone marrow. Dendritic cells act as "gate keepers" in the body's immune response process. They capture antigens, present them to T and B cells and signal the T and B cells whether or not the antigens should be considered as foreign. If the dendritic cells present the antigens as foreign, the T and B cells begin to destroy the invaders. This project will try to genetically alter the dendritic cells so that they no longer signal T and B cells to attack transplanted islets. The project builds on the long-standing research being done at the University of Pittsburgh on chimerism-the coexistence of donor and recipient cells-in transplant patients. These findings suggest that long-lived donor cells may help facilitate acceptance of transplanted organs, known as tolerance.

Top

Finding the Best Vectors

Principal Investigator - Neal DeLuca, PhD

Dr. DeLuca's project will research how the herpes simples virus (HSV) can be engineered to transfer genetic material to islets. HSV has great potential as a vector for islet cell gene therapy because it can be used in many different tissues, can be produced in great quantities, and can carry large genes. Dr. DeLuca's team will build on its earlier research on mutant forms of the virus to explore how therapeutic proteins made by HSV-transferred genes can alter the function of islet cell genes and affect islet cell survival.

Principal Investigator - Paul Robbins, PhD

Dr. Robbins' project will develop and test new vectors, both in islets in vitro and in animals following islet cell transplantation. The goal is to find the right vectors for human gene therapy clinical trials for diabetes.

Top

Preventing Nerve Damage

Principal Investigator - David Fink, MD
Joseph Glorioso, PhD

One of the most common and debilitating complications of diabetes is progressive nerve damage ("neuropathy"). Diabetic neuropathy can have many dangerous effects. Because it is difficult for some people with diabetes to feel pain in their limbs, they may ignore scratches or wounds that can become infected and eventually gangrenous. Nerve damage causes other people with diabetes constant pain in their limbs. Finally, damage to the nerves that control internal organs, such as the heart, can lead to life-threatening conditions including heart failure.

The project under the direction of Dr. Fink and Dr. Glorioso will attempt to prevent the progression of diabetic neuropathy by using a vector based on the herpes simplex type 1 virus to infect neurons with genes that produce small protein molecules called growth factors. The project will build on the investigators' previous research on animals, which indicates that treating animals with a vector that expresses nerve growth factor may prevent nerve damage in other models of neuropathy.

Top

Last Update
June 25, 2014
  • Increase/Decrease Text Size
  • Print This Page
Last Update
June 25, 2014
top