Atkinson, Mark A., PhD
Identifying the contribution of beta cell dysfunction and autoimmunity to the pathogenesis of type 1 diabetes
General Research Subject: Type 1 Diabetes
Type of Grant: Mentor Based Postdoctoral Fellowship
Project Start Date: July 1, 2012
Project End Date: June 30, 2016
Diabetes Type: Type 1 diabetes
Type 1 diabetes (T1D) is often described as an autoimmune disease resulting from interactions between genetic susceptibility and environmental factor(s) resulting in the destruction of insulin-producing beta cells. A major outstanding question in T1D research is, "What activates the immune response that leads to T1D?" This proposed Fellowship will explore whether beta cells, due to their unique biochemical requirements, bring about this immune attack and are not merely innocent bystanders. The notion of "Homicide versus Suicide" has long been of interest to the fellowship's mentors.
To investigate changes in beta cell function at the earliest stages of disease (prior to insulitis), islets from non-diabetic individuals at-risk of developing T1D (biochemical islet autoantibody positive) will be compared to normal age-matched individuals. The pancreatic tissues have been collected by the nPOD program with contributions from the two co-Mentors. Using a technique known as laser capture microdissection, islets will be removed from frozen pancreatic sections, with RNA isolated for analysis of gene expression for comparison between the aforementioned groups.
The goal is to identify whether biochemical pathways associated with metabolic demand/insulin secretion are increased in autoantibody-positive islets, and whether this increase correlates with the activation of genes associated with inflammation/attraction of immune cells. This proposal will test the hypothesis that beta cells are primarily responsible for initiating their own destruction and the genetic/environmental factors that precipitate T1D are those that increase insulin demand, impair beta cell function, or alter islet development. Such information is key to efforts seeking to prevent/cure T1D.
Mentor: Mark A. Atkinson, PhD Postdoctoral Fellow: Maigan Hulme, 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 research supported by this award is directed at understanding the causes of type 1 (insulin-dependent) diabetes. For over 40 years, investigators have understood that type 1 diabetes was an autoimmune disorder; a disease resulting from a self-directed and hence, self-destructive immune response against the insulin producing beta cells. A key event in that understanding emanated from autopsy based studies performed in the 1960’s and 70’s of the human pancreas obtained from individuals who died soon after their onsets of type 1 diabetes. Since that time period, a number of issues (e.g., decreased rates of autopsy, availability of animal models for type 1 diabetes, and thankfully…improved care for those at the diagnosis of the disease) lead to a dramatic if not profound decrease in studies of human pancreas.
Believing that clues as to the origins of type 1 diabetes may reside within studies of such tissues, five years ago, the Network for Pancreatic Organ donors with Diabetes (nPOD) was formed. To date, that effort (which is housed at the University of Florida) has obtained otherwise difficult to obtain tissues from over 200 persons with type 1 type 1 diabetes, as well as other individuals (e.g., type 2 diabetes, healthy controls, etc.).
In this project, the fellow will seek to understand what degree of beta cell dysfunction exists throughout the natural history of type 1 diabetes (i.e., before symptoms to periods long after disease onset). Special attention will also be given to understanding the exact mechanisms by which the immune response destroys beta cells. An improved understanding of these issues would help answer the question of, "what causes type 1 diabetes?" We believe that will be key to attempts to prevent and/or cure the disease as it will provide investigators vital knowledge as what exactly should be targeted when designing an ideal therapy.
If a person with diabetes were to ask you how your project will help them in the future, how would you respond?
One of the primary reasons a cure has not been identified for type 1 diabetes, nor a way to prevent the disease, is that we just don’t know what causes the disease from forming in the first place. In addition, the ability for human beta cells to replicate / regenerate within the pancreas has many questions surrounding it. I believe the successful address of these two questions would have a profound impact on someone with type 1 diabetes through the development of improved therapies. Beyond this, such information will be vital to preventing the disease in future generations.
Why is it important for you, personally, to become involved in diabetes research? What role will this award play in your research efforts?
For nearly 30 years, my research has been directed at addressing three questions: 1) what causes type 1 diabetes, 2) can we identify a means to predict those who will eventually develop the disease, and 3) can one find a way to prevent and/or cure the disease. While lofty goals, they have been a series of questions that have been a constant focus of my attention. My early interest in type 1 diabetes came through the exceptional mentoring I received as a young investigator, alongside of my spending time serving at a diabetes camp. Over the years, my passion for trying to help those with type 1 diabetes grew from interactions with hundreds of type 1 diabetes patients and their families; each, expressing the hope that the research we perform will make a difference. As a one time ADA post-doctoral fellow and ADA career development award winner (early 1990s), I want to use this award to help train the next generation of investigator; this, with the hope of providing mentoring to the degree I was able to receive.
In what direction do you see the future of diabetes research going?
I believe we are at a crucial type in diabetes research. Concerns over drug safety have never been higher, research support at a Federal level is excruciatingly difficult to obtain, we appear to be losing at least one if not two generations of future researchers (in large part, due to the aforementioned funding issue), pharmaceutical companies appear to be in a position of becoming even more risk averse, too many phase 3 (mature) drug trials have failed to meet their desired endpoints; the ominous thoughts to this area go on and on.
This is why I believe the ADA mentored fellow program is vital! Equipping young investigators who may be the next generation of leaders is key. One can hope that the short term bleak picture noted above will be just that, short term. Hence, young investigators could have the potential to flourish. I would also note that I believe we are in a period where translational (versus strict basic versus clinical research) will be given ever increasing respect and attention. Having either animal models, tissues, or innovative tools to address what once were basic questions, and translating those findings into clinical trials, with an ever increasing degree of confidence, will be key. It is for this reason that I (Mark Atkinson), will be working with my clinical colleague (Desmond Schatz), to co-mentor the fellow (currently Dr. Maigan Hulme).
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