Insulin, an essential regulator of blood glucose levels, is synthesized exclusively in a cells of the islets of Langerhans. In addition, beta cells have finely tuned mechanisms to sense the blood glucose level and to secrete insulin appropriately. These processes are regulated by a complex, but incompletely understood, transcriptional network. Recent work in rodent islet model systems has begun to unravel some of this complexity by identifying a number of key islet-enriched transcriptional activators and the conserved 5'-flanking region control elements to which they bind. However, there is very little information about the specific roles of islet-enriched transcription factors in human islet function. In addition, islet transplantation is an emerging therapy for type 1 diabetes, and we hypothesize that an improved understanding of the role of islet-enriched transcription factors in human islets may lead to interventions that enhance islet survival and function after transplantation. In response to this RFA, the proposed studies will focus on directly examining the significance of Pdx-1 and MafA, two transcriptional activators of the insulin gene with a combination of unique properties that predict a crucial regulatory role in human islet beta cell activity. Using in vitro and in vivo based experimental strategies successfully established in our laboratories to study these factors in rodent model systems, we propose two focused, interrelated goals: 1) define the expression of Pdx-1 and MafA in the human islet and their relationship to islet function and activity; 2) examine if islet transplantation alters Pdx-1 and MafA expression. This strategy will provide insight into the role of these transcription factors in human islet beta activity, will likely provide information that will be useful in generating acceptable islet-like cells for therapeutic treatment of diabetes, and should lead to new information relevant to islet transplantation in humans.
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| Saunders, Diane; Powers, Alvin C (2016) Replicative capacity of ?-cells and type 1 diabetes. J Autoimmun 71:59-68 |
| Conrad, Elizabeth; Dai, Chunhua; Spaeth, Jason et al. (2016) The MAFB transcription factor impacts islet ?-cell function in rodents and represents a unique signature of primate islet ?-cells. Am J Physiol Endocrinol Metab 310:E91-E102 |
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| Kayton, Nora S; Poffenberger, Gregory; Henske, Joseph et al. (2015) Human islet preparations distributed for research exhibit a variety of insulin-secretory profiles. Am J Physiol Endocrinol Metab 308:E592-602 |
| Hang, Yan; Yamamoto, Tsunehiko; Benninger, Richard K P et al. (2014) The MafA transcription factor becomes essential to islet ?-cells soon after birth. Diabetes 63:1994-2005 |
| Dai, Chunhua; Brissova, Marcela; Reinert, Rachel B et al. (2013) Pancreatic islet vasculature adapts to insulin resistance through dilation and not angiogenesis. Diabetes 62:4144-53 |
| Guo, Shuangli; Dai, Chunhua; Guo, Min et al. (2013) Inactivation of specific ? cell transcription factors in type 2 diabetes. J Clin Invest 123:3305-16 |
| Kaddis, John S; Hanson, Matthew S; Cravens, James et al. (2013) Standardized transportation of human islets: an islet cell resource center study of more than 2,000 shipments. Cell Transplant 22:1101-11 |
| Brehm, Michael A; Powers, Alvin C; Shultz, Leonard D et al. (2012) Advancing animal models of human type 1 diabetes by engraftment of functional human tissues in immunodeficient mice. Cold Spring Harb Perspect Med 2:a007757 |
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