- 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.
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
Zhu X, Gingrich MA, Soleimanpour SA, Stoffers DA, Gannon M: Cell cycle regulation of the Pdx1 transcription factor in developing pancreas and insulin-producing β cells. Diabetes Page: under revision, 2020
Mosleh E, Ou K, Haemmerle MW, Tembo T, Yuhas A, Carboneau BA, Townsend SE, Bosma KJ, Gannon M, O'Brien RM, Stoffers DA, Golson ML: Ins1-Cre and Ins1-CreER Gene Replacement Alleles Are Susceptible To Silencing By DNA Hypermethylation. Endocrinology 1: 161, Aug 2020.
Good AL, Haemmerle MW, Oguh A, Doliba NM and Stoffers DA. : Metabolic stress activates an ERK/hnRNPK/DDX3X pathway in pancreatic β cells. Molecular Metabolism 26: 45-56, Aug 2019.
Good AL, Cannon CE, Haemmerle MW, Yang J, Stanescu DE, Doliba NM, Birnbaum MJ, and Stoffers DA: JUND regulates pancreatic β cell survival during metabolic stress. Molecular Metabolism 25: 95-106, Jul 2019.
Juliana CA, Yang J, Cannon CE, Good AL, Haemmerle MW and Stoffers DA.: A PDX1-ATF transcriptional complex governs β cell survival during stress. Molecular Metabolism 17: 39-48, Nov 2018.
Peter Kropp, Jennifer Dunn, Bethany Carboneau, Doris Stoffers, and Maureen Gannon : Cooperative function of Pdx1 and Oc1 in multipotent pancreatic progenitors impacts postnatal islet maturation and adaptability. American Journal of Physiology-Endocrinology and Metabolism 314(4): E308-E321, Apr 2018.
Loyd C, Liu Y, Kim T, Holleman C, Galloway J, Bethea M, Ediger BN, Swain TA, Tang Y, Stoffers DA, Rowe GC, Young M, Steele C, Habegger KM, Hunter, CS : LDB1 Regulates Energy Homeostasis During Diet-Induced Obesity
Endocrinology 158 (5): 1289-1297, May 2017
Melissa Burmeister, Jacob Brown, Jennifer Ayala, Doris Stoffers, Darleen Sandoval, Randy Seeley, and Julio Ayala: The Glucagon-Like Peptide-1 Receptor in the Ventromedial Hypothalamus Reduces Short-Term Food Intake in Male Mice by Regulating Nutrient Sensor Activity. American Journal of Physiology-Endocrinology and Metabolism 313(6): E651-E662, Dec 2017.
Remsberg JR, Ediger BN, Ho WY, Damle M, Li Z, Teng C, Lanzillotta C, Stoffers DA, and Lazar MA: Deletion of Histone Deacetylase 3 in Adult Beta Cells Improves Glucose Tolerance via Increased Insulin Secretion Molecular Metabolism 6(1): 30-37, Nov 2017.
Rozo AV, Babu DA, Suen PA, Groff DN, Seeley RJ, Simmons RA, Seale P, Ahima RS and Stoffers DA: Neonatal GLP1R activation limits adult adiposity by durably altering hypothalamic architecture. Molecular Metabolism 6(7): 748-759, May 2017.
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Last updated: 09/22/2020
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