McDaniel, Michael L., PhD
Strategies to increase proliferation and maintain function in adult human beta cells
General Research Subject: Both Type 1 And Type 2 Diabetes
Focus: Islet Biology\Beta Cell Growth and Differentiation, Islet Biology\Metabolic Regulation, Transplantation
Type of Grant: Mentor Based Postdoctoral Fellowship
Project Start Date: July 1, 2009
Project End Date: June 30, 2013
The goal of this fellowship is to develop therapeutic strategies to increase the number of human beta cells for transplantation in type 1 diabetes or to increase beta cell mass in type 2 diabetes. Using two potential therapeutic drugs, the laboratory has identified communication between two major growth pathways, mTOR and Wnt/beta-catenin that is necessary to enhance growth and proliferation in isolated primary adult human islets.
Project 1 will use molecular approaches in isolated human islets to further characterize and confirm these results.
Project 2 will determine if manipulation of GSK-3 and mTOR signaling will promote beta cell function and prolif-eration by treating human islets with these therapeutic drugs prior to transplanting islets into diabetic mice.
Project 3: Preliminary data shows that GLP-1 and Exenatide (Byetta) stimulate regenerative processes in human islets.
This project will use molecular and pharmacological approaches to determine if GLP-1 or Exenatide mediate these effects through the GSK-3/beta-catenin and mTOR pathways.
Project 4: Culture and expansion of adult human islets results in dedifferentiation and loss of insulin content. This project will develop feasible in vitro strategies to optimize ?-cell proliferation and function by combining the use of GSK-3 inhibitors to promote proliferation and betacellulin, or other growth factors, to restore or maintain differentiation.
Project 5: Studies in the laboratory show a significant role for nitric oxide (NO) in beta cell replication. The role of endogenous NO and the GSK-3 signaling pathway in promoting beta cell proliferation will be investigated.
Mentor: Michael McDaniel, PhD Postdoctoral Fellow: Nidhi Rohatgi, PhD
What area of diabetes research does your project cover? What role will this particular project play in preventing, treating and/or curing diabetes?
The overall goal of my project is to identify growth pathways and develop feasible strategies to expand functional human beta cell mass in vitro and in vivo.
The goals of my research project are: 1) Study the crosstalk between Wnt/GSK-3/beta-catenin and GSK-3/TSC/mTOR pathways and determine their roles in enhancing human beta cell proliferation. 2) Determine if manipulation of GSK-3 and mTOR signaling will promote beta cell function, growth and proliferation in vivo. 3) Determine why with human islets Wnt3alpha fails to stimulate the Wnt pathway, and if Exenatide can correct this dysfunction through the GSK-3/beta catenin and mTOR pathways. 4) Develop strategies to restore and maintain beta cell function under in vitro conditions. 5) Investigate the role of endogenous nitric oxide (NO) on beta cell regenerative processes. Initially I will focus on project 3.
I anticipate that the results from this project will allow us to optimize the conditions required to induce beta cell growth and proliferation of human beta cells. This could enhance pre and post islet transplantation in Type 1 diabetes and prolong beta cell compensation in order to prevent glucose intolerance from developing into over Type 2 diabetes.
If a person with diabetes were to ask you how your project will help them in the future, how would you respond?
Diabetes results from an inadequate beta cell mass or insulin secretory dysfunction in order to maintain normal glucose levels. Determining the factors that affect and regulate human beta cell growth, proliferation and secretion will significantly contribute to developing therapeutic targets. Previous research in this laboratory revealed that strategies to stimulate rodent beta cell growth were rarely effective in human beta cells. The laboratory has developed treatment methods that can increase human beta cell growth and proliferation, but insulin content is decreased. The results from this project together with other diabetes research will provide us with the knowledge necessary to produce functional beta cells for transplantation in people with Type 1 diabetes and prolong beta cell compensation to prevent or delay the onset of Type 2 diabetes.
Why is it important for you, personally, to become involved in diabetes research? What role will this award play in your research efforts?
Worldwide, the occurrence of chronic human diseases is increasing at a distressing rate. Approximately 18 million people worldwide die every year from cardiovascular disease, for which diabetes and hypertension are major influencing factors.
Type 2 diabetes is a problem for many members of my family including both of my parents. Their daily suffering from this disease and dietary restrictions involved creates a personal passion to focus my research on diabetes. The ADA Mentor-Based Postdoctoral Fellowship will fulfill my desire to study diabetes and participate in understanding and finding a cure that would improve the lives of all people affected by this disease. In addition, the opportunity of learning from my mentor Dr. McDaniel and interacting with other diabetes researchers at Washington University will help me attain the skills and experience required to become an independent investigator that would contribute to diabetes research.
In what direction do you see the future of diabetes research going?
The future of diabetes research is going in many different directions. Understanding the regulation of stimulus secretion coupling, and proliferation of beta cells could provide potential therapeutic targets to delay or prevent the development of diabetes. One area of diabetes research which I find especially interesting is the study of the beta cell proliferation machinery and insulin secretion. Studying the different signaling pathways that affect DNA synthesis, cell cycle progression, proliferation of the beta cells, and insulin secretion will lead to identifying the key components that could help develop strategies for fighting diabetes.
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