Cobb, Melanie Houston, PhD
MAP kinases in beta-cell function
General Research Subject: Both Type 1 And Type 2 Diabetes
Focus: Islet Biology\Beta Cell Growth and Differentiation
Type of Grant: Mentor Based Postdoctoral Fellowship
Project Start Date: July 1, 2008
Project End Date: June 30, 2012
The fellow will study the molecular steps that allow glucose to control the rate of production of insulin in pancreatic beta cells. In particular, the fellow will focus on regulation of insulin gene transcription, the first step in hormone biosynthesis. Under normal conditions, glucose transmits a signal that changes the ability of proteins to induce an increase in insulin gene transcription. Under abnormal conditions, if glucose is elevated for 24 hours or more, as frequently occurs in noninsulin-dependent diabetes mellitus, glucose loses its stimulatory effect and begins to cause a decrease in the transcription of the insulin gene. The result is that over time less insulin is produced and glucose in the circulation increases even more. We have found that the activity of the enzyme ERK2, which acts as a cellular switch, is stimulated by glucose. ERK2 is required for both the increase in insulin gene transcription caused by glucose under normal conditions and the decrease in insulin gene transcription caused by abnormal conditions. ERK2 is a protein kinase, a type of enzyme that transfers phosphate from the ready form of cellular energy, ATP, to proteins, including those that regulate transcription, to change their functions.
Mentor: Melanie Cobb, PhD Postdoctoral Fellow: Eric Wauson, PhD
What area of diabetes research does your project cover? What role will this particular project play in preventing, treating and/or curing diabetes?
Pancreatic ß-cells are induced to synthesize and secrete insulin in response to increased blood glucose levels. The normal synthesis and release of insulin is prevented by the loss of properly functioning ß-cells in both type I and type II diabetes. The induction of ß-cell death, the inhibition of cell growth, and the decreased differentiation of new ß-cells are all potential causes for the loss of ß-cell numbers and cell mass. There is evidence that suggests that chronic high levels of blood glucose can cause both ß-cell death and decreases in insulin synthesis in the surviving ß-cells. ERK1/2 are protein kinases that are activated by glucose and are part of the signal transduction cascade that ultimately induces cellular changes, such as the increase in gene transcription and insulin synthesis that are caused by increases in blood glucose levels.
The regulation of ERK1/2 activity has been implicated in many cellular events, including cellular proliferation, differentiation, and death. Therefore, it is likely that the glucose-induced activation of ERK1/2 and the cellular changes that this causes help to control the total number and functions of ß-cells contained within the pancreas. My research will be designed to investigate how extracellular glucose regulates normal and pathological changes in gene expression by the regulation of ERK1/2 activity. The elucidation of the mechanism by which glucose regulates ERK1/2 and changes gene expression will potentially allow for the design of better drugs that could prevent the loss of ß-cells and/or enhance the ability of ß-cells to synthesize and secrete insulin.
If a person with diabetes were to ask you how your project will help them in the future, how would you respond?
Better treatments for diabetes are needed to help improve the quality of life for those suffering from this debilitating disease. The pancreatic ß-cells function to synthesize and secrete insulin in response to elevated blood glucose. ß-cells are lost and have impaired function in diabetic individuals, which leads to the continued elevation of blood glucose levels. To successfully design new treatments, it will be necessary to understand how the blood glucose levels are sensed by ß-cells and how this information is used during normal cellular states to regulate normal insulin synthesis and secretion. My project will focus on this question to identify additional steps for intervention.
Why is it important for you, personally, to become involved in diabetes research? What role will this award play in your research efforts?
To design new therapeutics for the treatment of diabetes, it will be important to determine how ß-cells sense glucose and how this information is transmitted into the nucleus of cells to cause the modulation of gene expression. The understanding of how glucose regulates ERK1/2 and other kinases and how these kinases regulate gene expression will likely be necessary to reach this goal. Since I have extensive experience in investigating how kinases regulate downstream targets, my skill set will be beneficial in reaching the indicated goals. Since we have expertise on the regulation of ERK1/2 and other kinases, my research environment will be conducive to achieving the above goals. This award will help to supply the necessary funds to pursue this research.
In what direction do you see the future of diabetes research going?
Since data suggests that a loss of pancreatic ß-cell mass causes diabetes, it will be important to understand the basic cellular mechanisms that cause the decrease in the number of ß-cells. Additionally, to replenish the pancreas with functional ß-cells, determining how to successfully transplant ß-stem cells will likely be a future goal of diabetes research. The understanding of the genetic program that induces these stem cells to differentiate into mature insulin synthesizing ß- cells will also likely be an important future direction in diabetes research. Finally, preventing the unwanted programmed cell death of ß-cells will require a basic understanding of the mechanisms by which this occurs.
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