Scott, Donald K.
ChREBP and glucose-stimulated beta cell proliferation
General Research Subject: Both Type 1 And Type 2 Diabetes
Focus: Islet Biology\Beta Cell Growth and Differentiation, Islet Biology\Beta Cell Transcription Regulation, Islet Biology\Metabolic Regulation
Type of Grant: Basic Science
Project Start Date: July 1, 2011
Project End Date: June 30, 2014
An important therapeutic goal for the treatment of both Type I and Type II diabetes is to be able to manipulate beta cell growth. Glucose itself causes beta cells to grow, but we don't completely understand how this happens. We have found that a glucose-sensing protein, called carbohydrate response element binding protein (or ChREBP for short) is required for glucose-stimulated beta cell growth. We also found that overexpression of ChREBP greatly amplifies the glucose effect on beta cell proliferation, making ChREBP an attractive, novel drug target. We propose to confirm these results by increasing and decreasing the abundance of ChREBP in human beta cells, and in a mouse model that has ChREBP removed. In addition, we found evidence that another protein factor, c-Myc, is regulated by ChREBP in response to glucose, and we hypothesize that glucose increases beta cell growth by acting through c-Myc, which then activates specific components of regulators of the cell's machinery (in this case, cyclins D2, E1 and A2) that makes cells divide -- the process that makes beta cells grow. Said another way, we think that glucose activates ChREBP, which activates c-Myc, which activates the cyclins, which makes the beta cells grow. Our Specific Aims are to 1) determine how increasing or decreasing the abundance of ChREBP affects glucose-stimulated beta cell division, and to 2) determine the role of c-Myc in ChREBP-dependent glucose-stimulated beta cell division. If our hypotheses are true, we will have identified ChREBP as an exciting new therapeutic target.
What area of diabetes research does your project cover? What role will this particular project play in preventing, treating and/or curing diabetes?
An important therapeutic goal for the treatment of both Type I and Type II diabetes is to be able to manipulate beta cell growth. Beta cells are sensitive to the presence of glucose, and responds by secreting insulin. In addition, glucose causes a small percentage of beta cells to replicate, but we don't completely understand how this happens, or why most of the beta cells do not divide. We have found that a glucose-sensing protein, called carbohydrate response element binding protein (or ChREBP for short) is required for glucose-stimulated beta cell growth. We also found that overexpression of ChREBP greatly amplifies the glucose effect on beta cell proliferation, making ChREBP an attractive, potential novel drug target. Because glucose naturally increases beta cell mass, we hope that targeting this pathway will provide therapies that will be tolerated by people with diabetes.
If a person with diabetes were to ask you how your project will help them in the future, how would you respond?
First of all, it is important to distinguish basic science from translational science. We are studying the underlying basic mechanisms by which glucose changes the ability of beta cells to replicate. There are many things we have to understand before we can move forward to try and find a drug that will enhance this process, and that is the basis of the grant award. If successful, we will move forward to set up a large scale screen of potential drugs, and carefully test them in a variety of what we call 'systems', that is in the Petri dish, in small animals, perhaps in monkeys before we test them for safety in humans. If we get to this stage, the idea would be that we would be able to force beta cells to replicate, or grow, as a therapy for Type 1 or Type 2 diabetes, or we would use a drug to replicate beta cells in Petri dishes prior to using them in transplant therapies.
Why is it important for you, personally, to become involved in diabetes research? What role will this award play in your research efforts?
I had a cousin who was blinded by diabetes when he was in his fifties.
This was his first symptom, so I am aware of suddenly the diseases can
impact people and how devastating the disease can be to families.
This award allows me to hire another person in my laboratory and provides the resources to perform experiments to better understand how glucose drives beta cells to replicate.
In what direction do you see the future of diabetes research going?
Technologies are advancing towards the ability to create a sort of
artificial insulin pump that can act more and more like a real
pancreas. This is an exciting area of research.
We are beginning to have a better understanding of how the immune system attacks beta cells, both in Type I and in Type 2 diabetes, and this is very exciting to us, as we will need to block cell death if beta cell replication therapies are to work.
We are getting a better understanding of how beta cells replicate. There are several approaches being attempted and this is a very exciting area of research. For example, we may be able to grow beta cells from stem cells, we may be able to convert other cells to beta cells, we may be able to use drugs to regenerate the remaining few beta cells of Type I patients, or repair the defective beta cells of Type 2 patients, and we may be able to coax beta cells isolated from donors to grow.
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