Wallet, Shannon Margaret
Osteoclast function in diabetes
General Research Subject: Type 1 Diabetes
Focus: Immunology, Other
Type of Grant: Career Development
Project Start Date: July 1, 2011
Project End Date: June 30, 2016
Diabetes Type: Type 1 diabetes
Increased bone loss diseases such as rheumatoid arthritis (RA) and periodontal disease (PD) is much higher in people with type 1 diabetes (T1D) and we do not currently understand why. In addition, we do not know if drugs which improve the bone loss are effective among diabetics with these debilitating diseases. Therefore future studies are needed to clarify the impact of different aspects of diabetes the observed bone loss. The long term goal of this project is to define mechanisms specific to the cells which are primarily responsible for the removing bone known as osteoclasts.
What area of diabetes research does your project cover? What role will this particular project play in preventing, treating and/or curing diabetes?
Diabetes mellitus afflicts over 21 million Americans, where bone or joint abnormalities are frequent co-morbidities, including rheumatoid arthritis (RA) and periodontal disease (PD). Data generated in this proposal will fill a significant gap in the current understanding of mechanisms associated with inflammatory bone and joint destruction as co-morbidities of diabetes mellitus.
The complexity of type 1 diabetes [T1D] itself and added complexity of bone and joint co-morbidities necessitates well-controlled and innovative approaches to assess the totality of potential causes. We have compelling data demonstrating a T1D-genotypic effect on osteoclast function in ex vivo murine models. We hypothesize that osteoclasts derived from T1D exhibit heightened sensitivity to stimulation which leads to increased bone resorption that is further augmented in vivo secondary to diabetes progression. Here we plan to characterize T1D-associated osteoclast-specific mechanisms that lead to increased bone and joint destruction under normoglycemic, hyperglycemic, or inflammatory conditions in both human and murine models of T1D. Specifically, osteoclast function and their role in diabetes-associated bone and joint pathogenesis will be studied in vivo using murine models of periodontal disease and arthritis with creative experimental designs to precisely dissect mechanisms of osteoclast dysfunction in T1D.
Current antiresorptive therapies directly or indirectly affect osteoclast function; however it is unclear if current antiresorptive drugs are effective in the context of intrinsic T1D-associated osteoclast defects or in the overtly diabetic microenvironment marked by hyperglycemia and inflammation. Therefore, a decisive interrogation of osteoclast-specific factors driving inflammation-induced bone loss in T1D is of immediate clinical importance. These findings will determine the necessity for and drive the development of more appropriate therapies for bone and joint pathologies occurring in diabetics. Just as the complex mechanisms of diabetes pathogenesis (immune and metabolic) have driven diversified strategies to pharmacologically target the illness, so too must the complex mechanisms of diabetes-associated bone and joint pathologies be the impetus for new discoveries
My training in diabetes research started in graduate school at UNC-CH under the direction of Roland Tisch. His commitment to his research and the disease processes involved in T1D was (and is) very contagious. He and his work ethic were exceptional models for my research career which continue to this day. After eight years in diabetes research, I am still fascinated by the immunological processes that lead to the manifestation of both Type 1 and Type 2 diabetes. In addition, I strongly feel that by unraveling the mysteries of these immunological processes that we can make a significant impact in the quality and quantity of the lives of those affected by the class of diseases which are under the umbrella of T1D and T2D.
If a person with diabetes were to ask you how your project will help them in the future, how would you respond?
As with all research, the most difficult challenge is explaining the importance of what you do. Although we don't directly investigate therapies or cures for diabetes, we strongly feel that our research will have a direct impact on therapies and cures currently being used and/or developed. But this is sometimes hard to explain and/or understand for those in the throws the conditions associated with diabetes. And rightly so as they are the ones who live with these issues day in and day out.
Diabetes is not a singular disease, but rather a classification of diseases whose clinical outcomes may be similar, but the mechanisms which result in the clinical manifestation are extremely complicated and extraordinarily different. Therefore, in order to provide the most appropriate and effective treatments and or therapies as well as to identify potential screening protocols and ultimately cures for disease, research involving numerous fields of study must be undertaken. In addition, the number of people directly and indirectly affected by the diabetes epidemic is growing everyday and although diabetes unto itself may not be a deadly disease its secondary complications most defiantly lead to increased morbidity and mortality. Therefore, additional avenues of research investigating these secondary complications, their mechanism and treatments in the context of diabetes are also needed in order to improve the quality and quantity of life.
It is these avenues of research which my interests lay. While I do strongly feel that research should continue into finding a cure of diabetes, I feel my best efforts could be put toward helping those afflicted with diabetes manage their lives and complications in a meaningful way to improve their quality of life in the short term. Specifically through evaluation of the efficacy of current treatments for these complications and the mechanisms associated with decreased efficacy in the hope of developing more effective and disease specific therapies.
Why is it important for you, personally, to become involved in diabetes research? What role will this award play in your research efforts?
When I joined the faculty at the University of Florida almost five years ago, I had two years of guaranteed support and so I knew I needed to secure extramural funding quickly. A colleague of mine, Clayton Mathews, mentioned the funding opportunities at the ADA. I have always been a strong supporter and member of the ADA, and I knew my area of interest was unique where the findings of our research could directly impact the quality of the lives of those affect. That along with being a brand new investigator made my needs and the goals of the ADA Junior Faculty Award a perfect fit. Because of my ADA Junior Faculty award, Colgate-Palmolive Corporation contacted me to perform some research looking at the inflammatory responses of Type 1 and Type 2 diabetics for product development. This has resulted in three years of corporate funding and two manuscripts describing altered mucosal immunity in people with type 1 diabetes as well as a potential medicament which could help control these aberrant responses. Currently I have an R01 in submission to the NIH NIDDK investigating the mechanisms associated with these findings. Similarly, the current ADA Career Development Award to investigate osteoclast (cells that breakdown bone) function in Type 1 and Type 2 diabetics is a direct result of additional data generated under my ADA Junior Faculty Award. Here we seek to be able to determine mechanisms of altered reactivity of osteoclasts to endogenous and exogenous stimuli and evaluate the affect of current therapies under the diabetic condition.
While diabetes research is my job and livelihood, it is also my passion. I honestly chose this avenue of research because I feel I can make a difference in the field and in the lives of those affected by diabetes. Although I don't directly investigate therapies or cures for diabetes, I strongly feel that my research will have a direct impact on therapies and cures currently being used and/or developed.
In what direction do you see the future of diabetes research going?
Diabetes research has made excellent strides in many areas including
prevention and treatment through investigations of genetics, cell
biology, immunology, education and behavior modification. Diabetes is
not one disease. It is a family of complex multifactorial disease
processes and the future of diabetes research should reflect this
knowledge. I envision a more systemic approach to diabetes research and
therapies in the future. It is critical that scientists and clinicians
understand the impact of diabetes complications upon patient health and
society as a whole. These complications not only exacerbate metabolic
defects but also present a massive burden upon the health care system.
It is imperative that investigators performing diabetes research keep in mind the many factors which directly or indirectly affect their primary area of interest. Likewise, it is important for clinicians, researchers, educators and patients to continually interact to ensure that novel research findings are practically and equitably applied. In addition, first hand interactions will facilitate the derivation new questions and concerns from mixed points of view. Based on the initiatives of many funding institutions today, it is clear that this is the current direction of diabetes research.
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