Objective
The purpose of this grant is to test and validate a new potential therapeutic to improve transplants as well as perform a screen to identify new targets. To do this, first testing the drug in mice to see if it improves blood glucose levels, insulin levels, and transplant outcomes is proposed as well as investigating the mechanisms by which this drug acts will be done. Secondly, identifying new targets that improve transplant outcomes will be investigated by conducting a genome-wide screen.
Background Rationale
Previous work in our lab found that knocking down HTR1F (a serotonin receptor) may improve islet transplant outcomes in mice. In order to study this further, we have also found a drug that antagonizes this receptor. I have done preliminary work to study the drug's effect using human islets transplanted into diabetic mice and found that the drug may improve the transplant outcomes. However, this drug requires more testing to improve the half life (so dosing can be less frequent) and I also need to investigate if the drug actually resulted in decreased cell death during the transplant. Because it is essential to improve transplant outcomes for type 1 diabetic patients, I would also like to identify new potential targets and investigate those as well. This proposal includes an aim to perform a screen to find some of these new targets that improve survival of beta cells during transplant.
Description of Project
Type 1 diabetes is an autoimmune disease that destroys the pancreatic beta cells and affects 1.4 million adults and 187,000 children. However, transplanting pancreatic islets is not an effective method because shortly after transplant, beta cells die off and makes this treatment ineffective for most patients. Therefore it is essential to find a method to improve beta cell survival during transplant. Our lab has performed a screen looking for targets that will improve transplant outcomes. One of these targets is a serotonin receptor called HTR1F. This project aims to investigate this target, test a drug that will act on this receptor, and perform a new genome wide screen to identify new targets that will potentially improve transplant outcomes.
Anticipated Outcome
I anticipate that I will find an improved dosing strategy for my drug and that I will see increased survival of beta cells after treatment with the drug. This work will also establish the mechanism by which this receptor acts to regulate beta cell survival. Finally, this work will also find new targets that improve transplant outcomes and hopefully lead to new drug developments that will help more type 1 diabetic patients qualify for transplants.
Relevance to T1D
Human pancreatic islet transplants are difficult because many beta cells die shortly after transplant and because of this, severely diabetic patients do not qualify. Additionally it is difficult to get human cadaver islet. Therefore, it is essential to find targets and drugs that can improve the efficiency of the transplant. By doing these preliminary studies in mice, we can establish this drug and target for HTR1F and hopefully increase beta cell survival and function. This proposal will also look at how this drug works and will do a screen for new targets that may improve beta cell survival in the transplant setting. In all, this work will hopefully establish new drugs or targets that will help improve transplants for type 1 diabetic patients.