Research Description
Infiltration of the pancreatic islet with activated immune cells occurs early in the development of type 1 diabetes (T1D), typically prior to clinical diagnosis. However, immune cell infiltration of the islet may occur for years with minimal impact on blood glucose levels. The factors leading to the rapid decline in islet mass and function prior to diagnosis are not well understood. Recently, there has been a focus on the insulin secreting ?-cell in the pancreatic islet to develop therapies which protect against immune-mediated dysfunction and destruction of islets in T1D. However, the role of the ?-cell in its own demise is not well understood. The goal of this study is identify novel mechanisms of immune-mediated ?-cell death and dysfunction and exploit these mechanisms to protect against the onset and progression of type 1 diabetes. To achieve this goal, I propose the following aims: 1) determine the role of protein kinase C delta (PKCdelta) in mediating inflammation-induced apoptosis in pancreatic ?-cells and 2) determine if loss of extracellular matrix interactions predisposes islets to apoptosis through activation of PKCdelta. The results of this study will identify a novel role for PKCdelta in mediating ?-cell death in T1D, particularly during immune cell infiltration of the islet when interactions with the extracellular matrix are disrupted. These results will support future studies to identify pharmacological modulators of PKCdelta which can be targeted to the ?-cell to preserve islet mass and function in individuals with a high risk for developing T1D.Research Profile
What area of diabetes research does your project cover? What role will this particular project play in preventing, treating and/or curing diabetes?This project primarily focuses on pre-type 1 diabetes, specifically the time period after autoimmunity has developed but before a person is clinically diagnosed with the disease. This is the time in disease progression that we seem to know the least about and is also the best time to intervene in disease progression to protect against further damage to the insulin-producing ?-cells in the islets of Langerhans. The goal of this study is to better understand the events that occur early in type 1 diabetes that lead to immune-mediated ?-cell death, with a focus on the roles the islet microenvironment and the ?-cell itself play in disease progression. This results from this project will identify novel pathways that lead to ?-cell destruction and will provide the foundation for future studies to determine if inhibiting these pathways protects against the onset of type 1 diabetes.
If a person with diabetes were to ask you how your project will help them in the future, how would you respond?The main focus of this project is to identify novel mechanisms regulating ?-cell death in type 1 diabetes, with the ultimate goal of being able to halt ?-cell death and disease progression. For a patient who has developed autoimmunity but has not been clinically diagnosed with type 1 diabetes, this work could lead to a therapy that would delay the onset on disease or prevent disease altogether when combined with an immunomodulatory therapy. For a patient who has established type 1 diabetes, this work could lead to a therapy that could be used in combination with islet transplantation therapy or strategies to expand existing ?-cells to protect against further immune-mediated damage and death. Ultimately, the more we know about disease onset and progression, better and more targeted therapies can be developed for each stage of disease. The results from this project will help us better understand early disease onset so that we can develop targeted therapies to delay or prevent onset of type 1 diabetes altogether.
Why important for you, personally, to become involved in diabetes research? What role will this award play?Coming from an engineering background, my career goals have always been to do something that will have a significant impact on human health, as engineers are always told that we can change the world. When I began working in diabetes during my postdoctoral studies, I was able to clearly see how my work could be translated into something that could have an impact on patients with type 1 diabetes. The current treatment option for patients with type 1 diabetes is lifelong injection of insulin and near constant glucose monitoring. There is a huge need for better therapies that remove dependence on insulin injections and reduce life-threatening complications. With the complexity of type 1 diabetes, it is clear that a multi-disciplinary approach could make significant gains in developing novel therapies. With my background in engineering and training in islet biology, I feel that I can make a significant contribution to the development of new therapies for patients with type 1 diabetes that will have a significant impact on their quality of life. The Junior Faculty Development Award will provide me with the resources necessary to jumpstart my research program and begin to investigate mechanisms regulating ?-cell death that could lead to the develop of novel therapies for type 1 diabetes.
In what direction do you see the future of diabetes research going?In recent years, it has become apparent that diabetes, both type 1 and type 2, is a very heterogenous disease. Each person has a distinct combination of genetic and environmental risk factors that can determine the course of the disease, as well the what treatments work best for that individual. As such, I believe the future of diabetes research will lie in personalized medicine, where genetics risk and phenotypic disease presentation are assessed for each patient to determine a customized plan of treatment. Current studies using single cell sequencing, genome-wide association studies, combined with studies on islet physiology, such as our work, in health and diabetes are paving the way for personalized medicine to become reality.