Objective
We have three main aims in this project. The first is to determine the role of our candidate gene SDF2L1 in beta cell models in response to stress. We will accomplish this by deleting the SDF2L1 gene in our model systems. The second aim is to use mouse models of type 1 diabetes to determine how well beta cells are protected when we delete SDF2L1. The third aim is a high-risk, high-reward approach to drugging the SDF2L1 protein as a way to create a therapy for type 1 diabetes. We will combine unique chemistry techniques to specifically target beta cells and not other cell types to reduce the amount of SDF2L1 or disrupt its normal functions.
Background Rationale
Our proposal is based upon a foundation of published and preliminary data supporting a negative role for SDF2L1 in β-cell survival. The labs of Dr. Cai and Dr. Kalwat each independently identified SDF2L1 in different experiments involving stressed β-cells. Other labs also published that reduction of SDF2L1 in β-cells might help protect β-cells in response to certain stresses. However, the way that SDF2L1 works in the β-cell is not well understood. In this research plan, we will characterize the functional role of SDF2L1 in regulating beta cell survival and how to protect beta cell against stress-induced cell death and autoimmunity.
Description of Project
Blood sugar (glucose) increases after eating a meal. Within the pancreas are clusters of cells called islets, which contain the insulin-producing beta cells. Insulin is a hormone that circulates in the blood and signals to muscle and fat to absorb glucose from the blood. In type 1 diabetes (T1D), the immune system attacks and destroys beta cells. This leads to a lack of insulin and causes high blood sugar (glucose) levels. High blood glucose for too long eventually causes blindness, nerve pain, and kidney disease. A major focus of T1D research is on preventing or slowing the immune attack on beta cells or replacing lost beta cells. Our project focuses on a gene called SDF2L1 that we predict has a negative impact on beta cell survival in T1D. We propose to attack this problem from multiple angles to better understand how SDF2L1 works and how we can target it with drugs to help protect beta cells during T1D.
Anticipated Outcome
This research proposal aims to deliver a therapeutic strategy for type 1 diabetes by inducing beta cell immune tolerance. Our work will help increase our knowledge of how SDF2L1 works in β-cells and also test its utility in mouse models of type 1 diabetes. We will also develop new methods to decrease the amount of SDF2L1 selectively in β-cells and drug-like chemicals that can disrupt the function of SDF2L1. Importantly, our successful completion of this work will facilitate applying these novel strategies to other candidates from our labs’ overlapping therapeutic β-cell gene candidates. The work will also spur collaborations with other diabetes researchers and potentially impact other autoimmune diseases.
Relevance to T1D
Maintaining long-term blood glucose control is the major goal for individuals with T1D. If we could protect existing β-cells in pre-T1D individuals, we could delay T1D diagnosis. Having as many tools as possible to fight autoimmunity in T1D, protect β-cells from stress, or improve their survival and function is critical. Even after transplantation with human islets or new stem cell-derived islets, tools that protect those β-cells from the immune system will still be needed. Our work directly addresses this need by targeting a gene that is implicated in the β-cell stress response. The ultimate goal of this proposal is to create a potential treatment for type 1 diabetes that advances current therapeutic strategies.