Project Details


Type 1 diabetes (T1D) is an autoimmune disease that poses significant challenges to afflicted individuals, to the development of effective therapeutic interventions and to public health initiatives at large. While the precise interactions between inherited susceptibilities and environmental factors that together trigger the disease remain to be elucidated in detail, T1D development is mediated by complex autoimmune processes that eventually destroy insulin-secreting beta-cells in the pancreas and lead to elevated blood sugar levels as well as serious disturbances of protein, fat and carbohydrate metabolism. Currently, no cure or effective prevention is available and despite insulin treatment, long-term complications such as kidney failure, heart attack and stroke are frequent. One of the major obstacles to the development of effective therapies is our incomplete knowledge about the pathological events that initiate and perpetuate T1D. This proposal is focused on the role of chemokines, a large family of secreted molecules that control multiple aspects of T cell traffic into the pancreas and beta-cell destruction. Although animal studies have convincingly demonstrated the utility of selected chemokines as therapeutic targets in T1D prevention, over 20 different chemokines have been associated with T1D development in humans and their precise contribution to T1D pathogenesis remains for the most part elusive. We recently developed a technical approach to visualize expression of ~40 mouse chemokines at the single cell level and have applied this methodology to identify relevant immune cell subsets that produce defined chemokines in the context of T1D in the mouse. Here, I propose to develop a similar approach for the identification of human chemokines and their principal cellular sources. We will first use an in vitro model of healthy human islets cultured in the presence and absence of inflammatory stimuli to assist in method development and to determine the identity of chemokines produced by beta- and other islet cells. Preliminary data indicate that there appears to be in fact a remarkable correspondence between chemokines expressed in the above human in vitro model and our in vivo animal studies. Subsequently, using human tissues made available through the JDRF-sponsored nPOD program, we will delineate, to the best of my knowledge for the first time, the chemokines produced by islet cells and islet-infiltrating immune cells in the pancreata of pre-diabetic and recent onset donors, healthy individuals and those with long-term T1D. Together with our animal studies, this proposal constitutes a unified approach to identify the pathological contribution of an entire family of molecules (chemokines) to T1D development and will assure that the future direction of our animal work is informed by a more detailed knowledge about human chemokines likely to be of pathological relevance and thus a potential therapeutic target in human T1D.

Effective start/end date1/03/1028/02/11


  • Juvenile Diabetes Research Foundation United States of America: $110,000.00


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