Objective
The overall objective of this research is to use advanced technology to compare the kinome in people at different stages of type 1 diabetes, in those at risk of diabetes, and whether it differs to people without diabetes. Specifically, we will use blood samples from these groups to test the kinome in different types of immune cells known to play major roles in type 1 diabetes.
Background Rationale
The kinome is a term used to refer to a family of proteins, called kinases, in our body. These kinases help our cells talk to one another and can affect how cells function. We can also look at how kinases effect cell growth, movement, and response to other cells. The kinome is essential for understanding health and disease.
The kinome can alter how immune cells function. Type 1 diabetes occurs when immune cells move into the pancreas and destroy the body’s own insulin producing beta cells. This process heavily relies on signalling proteins and pathways that alter cell function, cell movement from blood into tissues (like the pancreas), and communication between cells. Protein kinases that make up the kinome, are the largest family of signalling proteins in the body. Current evidence suggests that the kinome may influence the immune attack on the pancreas, playing a role in the development of type 1 diabetes. But we have only investigated a few individual protein kinases because the technology was not available to look more broadly at the kinome. We therefore, do not fully understand what kinases or pathways are important in the development of type 1 diabetes. This information could help us to 1) identify people at highest risk of developing type 1 diabetes and 2) find new drug targets to delay, stop, or reverse type 1 diabetes.
Through recent breakthroughs in type 1 diabetes, research is at an exciting stage. We are now screening the general populations to identify individuals “at risk” of future type 1 diabetes by home collection finger prick testing. This helps to prepare individuals for diagnosis and insulin-dependence, reduce how many people are admitted to hospital with life-threatening diabetic ketoacidosis, and offer the opportunity for those at risk to participate in clinical trials. In addition, Teplizumab, the first treatment to delay the onset of type 1 diabetes has been approved. A few drugs that target protein kinases have shown they can protect insulin-producing beta cells in type 1 diabetes. These drugs can be taken as tablets and have minimal side effects. This is desirable as no hospital admission or immune system suppression would be required. This research would be the first extensive study of the kinome in humans with and without type 1 diabetes and those at risk of future type 1 diabetes. In the short term, this research may improve our ability to determine “when” someone may develop type 1 diabetes and identify new drug targets to offer multiple therapy options for type 1 diabetes. In the longer term, we want to use this test to see if the kinome can monitor response to therapy. Some people do not respond to therapy in clinical trials, and we do not have a test that explains this. This technology can help to ensure people are offered a different treatment earlier to their benefit.
Description of Project
The kinome is a term used to refer to a family of proteins, called kinases, in our body. These kinases help our cells talk to one another and can affect how cells function. We can also look at how kinases effect cell growth, movement, and response to other cells. The kinome is essential for understanding health and disease.
The dysfunction of the kinome plays a key role in many diseases. Sometimes the kinome is overactive or underactive. This causes cells not to function or communicate properly. There has been a lot of success in treating diseases with drugs that target protein kinases. Most are used to treat different forms of cancer and show limited side effects. Only a few have been investigated in type 1 diabetes, but show very promising results. This shows that kinome dysfunction may be involved in the development of type 1 diabetes.
Type 1 diabetes is caused by immune cells mistakenly destroying the insulin-producing cells in the pancreas. Altered communication between immune cells and the kinome could speed up the development of type 1 diabetes.
For the first time, we seek to investigate the kinome family tree, in detail, in type 1 diabetes. This may reveal protein kinases or branches of the kinome that are critical and specific to type 1 diabetes. In the past this was not possible, because the technology was not available. We aim to compare the kinome in blood samples from people at risk of future type 1 diabetes, people living with type 1 diabetes, and people without diabetes.
This project has two main outcomes:
1). To better identify people at highest risk of developing type 1 diabetes in the future.
2). To identify unique drug targets that will delay, stop, or reverse the development of type 1 diabetes.
We hope this project will speed up the progress towards delivering therapies to cure/prevent type 1 diabetes.
Anticipated Outcome
For the first time, we will compare the kinome in three groups. People without diabetes, people at risk of type 1 diabetes, and people living with diabetes. We expect that we will identify key differences in the activity and function of the kinome between these groups. This will tell us about the role of the kinome in diabetes development and how it can tell us about risk of diabetes. It will also allow us to identify many kinase drug targets to treat type 1 diabetes. This approach will speed up the process of studying kinase drug targets in clinical trials within 5 years. Testing the kinome in clinical trials may also be able to tell us why some people respond to a given therapy and why others do not. We hope in 5-10 years, this research will have helped to provide more treatment options for type 1 diabetes. This will initially progress research towards insulin-free T1D with the ultimate goal of T1D prevention.
Relevance to T1D
About 8.5 million people are living with type 1 diabetes worldwide. In the UK, about 8% of people with diabetes have type 1 diabetes. This is about 400,000 people. Each year, doctors diagnose more than 3,000 children and a similar number of adults. In the past, type 1 diabetes was considered a childhood condition, but we now know this not to be the case. This study will focus on improving staging of risk in children and adults as well as, identifying potential novel pathways for future therapy.
The best biomarkers used to identify people at risk of type 1 diabetes are proteins called "autoantibodies." The presence of autoantibodies in the blood tells us that the immune system has been “switched on” to attack insulin-producing beta cells. But these autoantibodies cannot tell us “when” someone will develop type 1 diabetes. We need additional biomarkers to help tell us when type 1 diabetes will happen. This will provide individuals with more information and time to prepare for insulin dependence. This could prevent people being admitted to hospital with life-threatening diabetic ketoacidosis (DKA).
Providing more treatment options for type 1 diabetes is crucial. It is unlikely one drug will work for everyone. Having a range of drug options allows a therapy to be tailored to a given person. This will ensure the correct drug gets prescribed to the person most likely to respond to the drug. This research project will reveal many drug targets that can be further investigated in clinical trials. This will take speed up the process of being able to offer tailored therapy to delay/prevent/reverse type 1 diabetes in the near future.