- 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
Key words: Diabetes, insulin, beta cell, pancreas development, transcriptional regulation, signal transduction.
Description of Research
The Stoffers laboratory is a basic biomedical research group, encompassing clinical and basic postdoctoral fellows, MD, MD-PhD and PhD graduate students, and undergraduates, all striving to understand the development, maintenance and regeneration of pancreatic islet beta cells that produce the hormone insulin so critically required for normal glucose homeostasis.
Reduced number and function of insulin-secreting beta cells underlies the progression of all forms of diabetes, underscoring the translational relevance of deciphering molecular pathways regulating the formation, growth, and function of beta cells. The transcriptional networks critical for the proper development, differentiation, and expansion of beta cells, work through islet enhancers, super enhancers and active promoters that form 3- dimensional hubs. The homeodomain transcription factor Pdx1 is a critical member of the beta cell transcriptional network during embryonic beta cell formation and in postnatal beta cell function. Pdx1 is mutated in monogenic forms of human diabetes and plays critical roles in early pancreas specification, regulation of organ size, and in beta cell formation, proliferation, and identity.
We use genomic and proteomic approaches integrated with genetic mouse models and primary human islet investigations to define the partners of PDX1 and its downstream transcriptional targets. The exploration of PDX1 partners and targets takes us into new areas including mechanistic investigations of beta cell development, metabolism and postnatal cell survival.
Our current projects include:
1. The Stoffers laboratory recently identified the polyC binding protein (PCBP) family of RBPs as important players in the post-transcriptional regulatory landscape of pancreatic beta cells. We recently found that the PCBP hnRNPk translationally upregulates JUND in islets exposed to glucolipotoxicity conditions (high glucose and free fatty acid; GLT) and that depletion of JUND in β cells reduces oxidative stress and apoptosis caused by GLT. We are exploring the in vivo roles of PCBP1 and PCBP2 using genetic mouse models and we are using proteomic and genetic approaches to investigate the hnRNPk complex.
2. We recently identified a novel PDX1 stress inducible complex (es) positioned over CARE sites and involving ATF4 and ATF5 that regulates expression of stress and apoptosis genes to govern β cell survival. We are characterizing these targets comprehensively and we are beginning to pursue the specific roles of novel targets in the beta cell, with a particular focus on the transaminase Gpt2.
3. We hypothesize that PDX1-Onecut1 (OC1) interactions, in part mediated by their intrinsically disordered protein regions (IDPRs), regulate Pdx1 stability, cell cycle progression, and pancreatic endocrine differentiation during development. Our current efforts on this project are directed at (1) determining the mechanisms whereby Pdx1 and Oc1 cooperate to establish a chromatin landscape permissive for endocrine differentiation and proliferation, (2) Defining the roles of the Pdx1 and Oc1 IDPRs in protein-protein interaction and endocrine differentiation, and (3) Defining the molecular mechanisms by which the Pdx1 C-terminal domain regulates protein stability and function during pancreas organogenesis and endocrine differentiation. This project is a highly collaborative effort with the Gannon laboratory at Vanderbilt University, the Soleimanpour laboratory at the University of Michigan, and the Gadue laboratory at the Children’s Hospital of Philadelphia (CHOP).
4. We have identified the cullin3 based E3 ubiquitin ligase substrate adapter SPOP as a protein partner that interacts with the PDX1 C-terminus. Our current efforts are positioning SPOP in ability of low glucose to destabilize PDX1. We are analyzing the in vivo consequences of inactivating Spop in the beta cell, using a conditional Spop allele generated by our group.
5. The Stoffers Lab is always ready to help our clinical and genetics colleagues by investigating the mechanisms by which human diabetes mutations influence PDX1 functions.
6. The Islet Cell Biology Core (ICBC) directed by Dr. Stoffers is an important component of the NIH funded Penn Diabetes Research Center and plays a central role in the Human Pancreas Analysis Program (HPAP) efforts in both type 1 and type 2 diabetes. The ICBC performs islet physiological phenotyping of all HPAP donor islet preparations. Recent findings have highlighted the role of alpha cell defects in islets from single autoantibody GADA+ donors and in the differences in function of islets from non-diabetic and diabetic donors of different ethnicities. We are now testing hypotheses about the roles of specific dysregulated pathways and genes in alpha cell physiology.
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
Sabyasachi Sen, PhD Postdoctoral Fellow
Bareket Daniel, PhD Postdoctoral Fellow
Xiaodun Yang, MD, PhD, Postdoctoral Fellow
Matthew Haemmerle, Graduate Student
Alexis Oguh, Graduate Student
Andrea Scota, Research Specialist
Andrea Rozo, Resource Technologist
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: 04/23/2022
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