Morris, Margaret Allison
The role of macrophage 12/15-lipoxygenase in the innate autoimmune responses of type 1 diabetes.
General Research Subject: Type 1 Diabetes
Focus: Immunology, Pediatrics\Type 1
Type of Grant: Junior Faculty
Project Start Date: July 1, 2011
Project End Date: June 30, 2014
Type 1 diabetes (T1D) is an autoimmune disease in which the body's immune cells systematically destroy the insulin-producing beta cells that are located in the pancreas. One of the factors involved in the development of this disease is an enzyme called 12/15-lipoxygenase (12/15-LO). It generates products that cause inflammation in many types of tissues, including the pancreas. In a strain of mice prone to develop spontaneous T1D (which closely mimics that of humans), the absence of 12/15-LO leads to protection against the development of diabetes. This study proposes to determine how this enzyme affects macrophages, a type of immune cell that produces 12/15-LO and is involved in the development of T1D. To accomplish this, mice that specifically lack the 12/15-LO enzyme in macrophages will be studied to see if they develop spontaneous T1D. If macrophage production of 12/15-LO is one of the factors leading to autoimmune diabetes, then these mice may also be protected from developing T1D. Additionally, this study will look at how the enzyme deficiency affects other immune cells that interact with the macrophages. These studies should provide a greater understanding as to the role of this enzyme in the development of T1D, and aid in the development of therapeutic targets for T1D.
What area of diabetes research does your project cover? What role will this particular project play in preventing, treating and/or curing diabetes?
My research investigates the role of a particular enzyme (12/15-lipoxygenase) in the development of type 1 diabetes. This enzyme appears to be responsible for initiating early inflammation, which may lead to the development of autoimmunity in type 1 diabetes. This project will determine the mechanism by which certain cells in the immune system produce 12/15-lipoxygenase, and how this production affects the development of autoimmune responses in type 1 diabetes.
It is hoped that the results of this project will lead to a better understanding of the interactions between cell types in the pancreas leading to the development of type 1 diabetes. Currently, some of my collaborators are developing specific inhibitors that target the 12/15-lipoxygenase enzyme. Once we know how the enzyme functions naturally, we will understand how inhibiting this enzyme affects the development of diabetes. We believe by combining therapies that inhibit the autoimmune response with those that increase beta cell health and insulin production, we will stop the progression of, and possibly cure type 1 diabetes.
If a person with diabetes were to ask you how your project will help them in the future, how would you respond?
My project is designed to dissect the mechanisms by which 12/15-lipoxygenase (a proinflammatory enzyme) affects the function of cells in the immune system, thereby priming the autoimmune response. The cells that act the earliest in a developing immune response, whether it is appropriate or inappropriate, are called innate immune effectors. These effector cells include macrophages and natural killer cells. Macrophages are known to produce 12/15-lipoxygenase, which increases the level of inflammation, and subsequently activates the immune system. Natural killer cells have been shown to react to products produced by macrophages and be involved in type 1 diabetes development. I hope that my project provides the background information needed to tell us how the 12/15-lipoxygenase affects diabetes progression. With my collaborators, we believe that specific inhibitors of 12/15-lipoxygenase may inhibit the early stages of the autoimmune response without global immune suppression seen with the currently available treatments. We hope that these inhibitors will be effective in both newly diagnosed patients, and those that have been suffering with type 1 diabetes for longer periods of time. In both cases, it is likely necessary that combination therapies may be required to combat type 1 diabetes, as it is likely that patients also need a means of jumpstarting beta cell regeneration and increased insulin production to fully cure type 1 diabetes.
Why is it important for you, personally, to become involved in diabetes research? What role will this award play in your research efforts?
I became interested in diabetes research for several reasons. My best
friend from graduate school has been living with type 1 diabetes for 26
years, and given my love of immunology, it seemed natural for me to
become involved in type 1 diabetes research. I am also struck by the
increased number of young children afflicted with type 1 diabetes. It
breaks my heart that these young children must suffer through blood
glucose monitoring without being capable of understanding what is wrong
The American Diabetes Association Junior Faculty Award will enable me to establish my own laboratory, and place me on track to apply for additional awards that will fund the continuation of my research. This award will allow me to further publish my results, which is crucial for scientific growth and outreach to both scientists and the general public. Furthermore, this award will allow me to share my results at national meetings, like the American Diabetes Association Scientific Sessions, which provides a means of developing stronger relationships with collaborators both old and new. The Junior Faculty Award will also allow me to begin mentoring young scientists. I firmly believe that one of the most important responsibilities of being a scientist is to mentor future generations of scientists.
In what direction do you see the future of diabetes research going?
Both type 1 and type 2 diabetes result from extensive amounts of
inflammation. I see future research attempting to thwart the
development of both forms of the disease by understanding and combatting
this inflammation. My research project looks directly at one source of
inflammation. However, in many cases, decreasing inflammation alone
may not be enough. In these cases, combination therapies that also
address the health of the insulin-producing beta cells will also be
prudent. It is likely that by halting damaging inflammation and
supporting beta cell health, diabetes can be better treated, if not
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