Mirmira, Raghavendra G.
Beta cell growth and survival in diabetes
General Research Subject: Both Type 1 And Type 2 Diabetes
Focus: Islet Biology\Apoptosis, Islet Biology\Beta Cell Growth and Differentiation, Islet Biology\Beta Cell Transcription Regulation
Type of Grant: Mentor Based Postdoctoral Fellowship
Project Start Date: July 1, 2011
Project End Date: June 30, 2015
The proposed mentor-based minority postdoctoral fellowship will focus on the training of a postdoctoral fellow in the laboratory of an established islet researcher, Dr. R. Mirmira at Indiana University. The objective of the Mirmira laboratory is to elucidate the mechanisms governing the function and survival of the insulin-producing beta cell in the context of diabetes mellitus. Projects in the Mirmira laboratory focus on gene regulation in the islet, pathways that lead to stress on the islet in the setting of type 1 diabetes, and on the mechanisms of islet dysfunction in the setting of type 2 diabetes. Three general project areas are available to the postdoctoral trainee, including (1) The role of transcriptional cofactor Set7/9 in beta development and function, (2) the role of eIF5A in early islet dysfunction in autoimmune diabetes, and (3) the role of enzyme 12-LO in islet survival in states of insulin resistance. The underlying philosophy of the proposal is based on the individualized selection of research projects to match the training needs of the postdoctoral fellow, with subsequent refinement and focus as progress is evaluated. The training plan includes direct interactions between mentor and fellow, group interactions with the lab members and faculty in the Diabetes Center, an enrichment program consisting of seminar series and journal clubs, and an oversight committee to ensure the unbiased training of the fellow. The proposed program is intended to train a minority postdoctoral fellow to lead a successful long-term academic career in diabetes research.
Mentor: Mirmira, Raghavendra M.D., Ph.D. Postdoctoral Fellow: Adewola, Adeola
What area of diabetes research does your project cover? What role will this particular project play in preventing, treating and/or curing diabetes?
It is widely known now that the prevalence of diabetes has been rising to alarming rates in the United States. The American Diabetes Association reports that almost 24 million Americans (8% of the US population) have type 1 or type 2 diabetes, and the Centers for Disease Control reports that one in three Americans born in 2000 will develop diabetes in his/her lifetime (should the current trends continue). At the cellular level, the hallmark of type 1 diabetes is a defect in islet ? cell function, whereas defects in adipocytes, muscle, and liver have been traditionally viewed as paramount in the pathogenesis of type 2 diabetes. However, it is now recognized that defects in insulin secretion from islet ? cells is also vital in the continuum to frank type 2 diabetes. Data from the United Kingdom Prospective Diabetes Study suggest that islet function begins its decline many years prior to the diagnosis of type 2 diabetes, and continues for many years thereafter, contributing to an increasing need for antidiabetic drug therapy. Thus, it is becoming clear that strategies aimed at treating type 2 diabetes (and certainly type 1 diabetes) should consider targeting islet function and survival. In this project, we propose to study two aspects of islet ? cell biology that may allow for more efficient treatment of both type 1 and type 2 diabetes. In the first, we will study the enzymes deoxyhypusine synthase (DHS) and 12-lipoxygenase (12LO), which appear to mediate islet dysfunction in response to stress in states of diabetes. In the second, we will study how cells known as endothelial colony forming cells (ECFCs) support the function of islets, and how they could be utilized in islet transplantation strategies to improve outcomes.
If a person with diabetes were to ask you how your project will help them in the future, how would you respond?
Our project will identify the manner in which DHS and 12LO lead to islet dysfunction and death in the setting of both type 1 and type 2 diabetes. We feel that a better understanding of the pathways by which these enzymes lead to islet dysfunction and death will allow us to more rationally use inhibitors, or small molecule drugs, to block one or both of these enzymes. Blocking these enzymes may allow islet function recovery in diabetic states, and thereby reverse the high blood sugars and their detrimental effects. In the case of ECFCs, our project may allow us to use these cells (derived from human cord blood) to support islets during transplantation.
Why is it important for you, personally, to become involved in diabetes research? What role will this award play in your research efforts?
I have been engaged in diabetes research since the inception of my research career in graduate school. My passion for diabetes came from the enthusiasm and genuine commitment that my late PhD mentor, Dr. Howard Tager, displayed. Dr. Tager provided me not only the guidance to a successful research career, but showed me how basic research can impact individual lives, especially those of people with diabetes. The research I did as a graduate student has now translated into the development of insulin analogs that are far superior to the traditional short and intermediate-acting insulins of that day. This connection between research and its impact on peoples' lives is what led me to also pursue clinical training in diabetes. Today, I use my research skills to discover potentially new pathways for therapy, and my clinical skills to deliver those therapies. This award is important to me in much the same way that Dr. Tager was influential in my career. This award will allow me to train an aspiring postdoctoral fellow to become the best scientist she can be-and in the process, instill a passion for diabetes research.
In what direction do you see the future of diabetes research going?
I feel the future of diabetes research is heading in the direction of
drug discovery and and cellular therapies. Whether the goal is to
regenerate new islets, preserve islet function/survival, enhance muscle,
fat, and liver insulin sensitivity, or find ways to suppress the immune
system, it is clear to me that the best research is now aimed at
identifying new proteins that effect these pathways and finding
molecules that inhibit or activate these proteins, or identify new cell
types that can support the growth and function of islets. This
'translational' direction of research has been the driving force of much
of NIH, ADA, and JDRF funding in recent years-and for good reason: the
goal of diabetes research is to find the best therapies, possibly
cures, for people with all forms of diabetes. The research proposed
with this award is clearly in line with my vision for the future of
diabetes research. We are especially excited about what the future
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