- transcription factors and signal transduction
- embryonic development and adult regeneration of the endocrine pancreas
- relationship of defects in these pathways to the pathophysiology of diabetes mellitus, a disease caused by a deficiency in the production or action of insulin
Diabetes, insulin, beta cell, pancreas development, transcriptional regulation, signal transduction.
Description of Research
Research in our laboratory focuses on the embryonic development and adult regeneration of the endocrine pancreas, and the relationship of defects in these pathways to the pathophysiology of diabetes mellitus, a disease caused by a deficiency in the production or action of insulin. The beta cells of the endocrine pancreas are the only source of insulin production in the body- therefore the regulation of beta cell mass is pivotal to the development of diabetes and successful therapies aimed at correcting diabetes must impact beta cell growth and/or function. Further support for this focus derives from genetic studies linking monogenic forms of human diabetes to mutations in transcription factors that regulate the development of beta cell mass. A model example is the homeobox transcription factor, IPF-1/PDX-1, that plays critical roles in embryonic pancreas development and in differentiated islet beta cell function in the adult endocrine pancreas. Using cutting edge molecular methods, yeast two hybrid libraries, transgenic and knock-out mice, cDNA microarray, chromatin immunoprecipitation, human genetics, and genomic and proteomic approaches, our current projects include:
1. Characterization of a novel PDX C-terminus Interacting Factor, PCIF1, identified in a yeast two-hybrid screen. PCIF1 is a novel nuclear factor that recruits Pdx1 into a cullin3 based E3 ubiquitin ligase for polyubiquitination and proteasomal degradation. Biochemical, molecular, in vivo and human genetics approaches are being applied to elucidate the role of this novel regulatory molecule.
2. Examining the molecular mechanisms by which the incretin hormone GLP-1 stimulates expansion of beta cell mass, with a particular emphasis on signal transduction and the identification of molecular mechanisms whereby GLP-1 promotes beta cell regeneration and regulates PDX expression.
3. Elucidating molecular mechanisms underlying islet compensation for diet-induced insulin resistance.
4. Identifing targets of Pdx1, Pbx and Meis homeodomain factors in the pancreatic ß cell.
Rotation Projects for 2008-2009
Lab rotation projects are available in all of the major areas described above. Please arrange for an appointment to discuss.
Doris A. Stoffers, MD, PhD, Principal Investigator
Jiangying Liu, PhD Postdoctoral Fellow
Ada Po Man Suen, PhD Postdoctoral Fellow
Scott Soleimanpour, MD, Postdoctoral Fellow
You Wang, Postdoctoral Fellow
Jennifer Oliver-Krasinski, Graduate Student
Mira Sachdeva, Graduate Student
Katy Claiborn, Graduate Student
Cynthia Khoo, Graduate Student
David Groff, Research Specialist
Juxiang Yang, PhD, Research Specialist
Benjamin N. Ediger, Aiping Du, Jingxuan Liu, Chad Hunter, Erik Walp, Jonathan Schug, Klaus Kaestner, Roland Stein, Doris Stoffers*, and Catherine Lee May*
*these authors contributed equally: Islet-1 is essential for postnatal pancreatic β-cell function
Diabetes under revision 2014 Notes: * denotes equal authorship.
Scott A. Soleimanpour; Aditi Gupta; David N. Groff; João Fadista; Lynn A. Spruce; Jake A. Kushner; Leif Groop; Steven H. Seeholzer; Brett A. Kaufman; Hakon Hakonarson; and Doris A. Stoffers: The diabetes susceptibility gene Clec16a regulates mitophagy
Cell in press 2014.
Chong Wee Liew, Anke Assmann, Andrew T Templin, Jeffrey C Raum, Kathryn L. Lipson, Sindhu Rajan, Jiang Hu, Dan Kawamori, Iris Lindberg, Louis Philipson, Nahum Sonenberg, Allison B. Goldfine, Doris A Stoffers, Raghavendra G. Mirmira, Fumihiko Urano & Rohit N. Kulkarni: Insulin Regulates Carboxypeptidase E by Modulating Translation Initiation Scaffolding Protein eIF4G1 In Pancreatic beta-cells
Proceedings of the National Academy of Sciences, USA in press 2014.
Eric P. Smith, Zhibo An, Constance Wagner, Alfor G. Lewis, Eric B. Cohen1, Bailing Li, Parinaz Mahbod, Darleen Sandoval, Diego Perez-Tilve, Natalia Tamarina, Louis H. Philipson, Doris A. Stoffers, Randy J. Seeley and David A. D’Alessio: The role of β-cell GLP-1 signaling in glucose regulation and response to diabetes drugs Cell Metabolism in press 2014.
Wilson-Pérez HE, Chambers AP, Ryan KK, Li B, Sandoval DA, Stoffers D, Drucker DJ, Pérez-Tilve D, Seeley RJ: Vertical Sleeve Gastrectomy is Effective in Two Genetic Mouse Models of Glucagon-like Peptide-1 Receptor Deficiency. Diabetes Page: [Epub ahead of print] Feb 22 2013
Baeyens L, Lemper M, Leuckx G, De Groef S, Bonfanti P, Stangé G, Shemer R, Nord C, Scheel DW, Pan FC, Ahlgren U, Gu G, Stoffers DA, Dor Y, Ferrer J, Gradwohl G, Wright CV, Van de Casteele M, German MS, Bouwens L, Heimberg H.
: Transient cytokine treatment induces acinar cell reprogramming and regenerates functional beta cell mass in diabetic mice.
Nature Biotechnology [Epub ahead of print], Nov 2013.
Henley K, Stanescu, D, Maulis, Schug J, Wright CVE, Stoffers DA*, Gannon M*
*contribution: Onectu1 and Pdx1 coordinate during pancreatic organogenesis to regulate genes required for postnatal islet function. in preparation in preparation 2013.
Tao Gao, Brian McKenna, Changhong Li, Maximilian Reichert, James Nguyen, Tarjinder Singh, Chenghua Yang, Archana Pannikar, Nicolai Doliba, Tingting Zhang, Doris A. Stoffers, Helena Edlund, Franz Matschinsky, Roland Stein, and Ben Z. Stanger: Pdx1 maintains β-cell identity and function by repressing an alpha-cell program
Cell Metabolism in press 2013.
Wang Y, Liu J, Liu C, Naji A and Stoffers DA: MicroRNA-7 regulates the mTOR pathway and proliferation in adult pancreatic β-cells. Diabetes published on line Dec 6, 2012, Dec 2012.
Khoo, C, Yang J, Weinrott SA, Kaestner KH, Naji A, Schug J, Stoffers DA. : The Pdx1 cistrome of pancreatic islets. Molecular Endocrinology 26(3): 521-33, March 2012.
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Last updated: 04/23/2014
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