A hallmark of both type 1 and type 2 diabetes is the failure of pancreatic beta cell mass to produce sufficient insulin to meet metabolic demands. PDX-1 (Pancreas Duodenal homeoboX-1) is a homeodomain transcription factor that is pivotally positioned in the transcriptional hierarchy governing the development of beta cell mass. Whereas homozygous mutation of PDX-1 causes pancreatic agenesis in both mice and humans, heterozygous PDX-1 gene mutations impair beta-cell function and survival, leading to glucose intolerance and diabetes in mice and in humans (early [MODY4]- and late-onset type 2 diabetes). PDX-1 haploinsufficiency markedly impairs the islet compensatory response in several insulin resistance mouse models, due to impaired insulin secretion and/or beta cell mass expansion and beta cell survival. Much remains to be learned about the molecular mechanisms whereby PDX-1 regulates gene transcription and about the relevant PDX-1 targets that mediate its critical actions on the beta cell. We hypothesize that the PDX-1 C terminus, which is mutated in familial human type 2 diabetes, is required for normal bea cell expansion in the late fetal/early neonatal period. Further, we hypothesize that the identification of PDX-1 targets in the adult beta cell will give insight into mechanisms of islet compensation in patients with type 2 diabetes. These hypotheses will be tested as follows:
Aim 1 : Determine the in vivo and molecular role of the PDX-1 C-terminus: We will characterize PDX-1 Cterm-/- mice that express a prematurely truncated PDX-1 lacking the C-terminal domain by assessing lineage specification, beta cell proliferation and survival, critical markers of beta cell identity, and insulin secretion. Biochhemical experiments will address the role of the C-terminus in protein turnover, subcellular localization and target promoter occupancy. Point mutagenesis of the C-terminus and a rapid biological screen of selected mutations in zebrafish will be carried out.
Aim 2 : Identify PDX-1 transcriptional targets in the adult beta cell. We will characterize a novel PDX-1 enhancer located upstream of a gene with high relevance to the postnatal functions of PDX-1, and we will explore its role in mediating the beta cell trophic effects of GLP-1 and in islet compensation for insulin resistance. Further, we will perform a """"""""ChIP on chip"""""""" analysis using adult mouse pancreatic islet chromatin. A complementary bioinformatics approach will focus on a subset of PDX-1 proliferation related target genes that are regulated by PDX-1: PBX heterodimers. Together, the proposed studies will address important questions about the functions of PDX-1 in beta cell biology, with particular relevance to its role in beta cell compensation for insulin resistance.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Program Projects (P01)
Project #
Application #
Study Section
Special Emphasis Panel (ZDK1)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Pennsylvania
United States
Zip Code
Kim, Yong Hoon; Marhon, Sajid A; Zhang, Yuxiang et al. (2018) Rev-erb? dynamically modulates chromatin looping to control circadian gene transcription. Science 359:1274-1277
Juliana, Christine A; Yang, Juxiang; Cannon, Corey E et al. (2018) A PDX1-ATF transcriptional complex governs ? cell survival during stress. Mol Metab 17:39-48
Barnoud, Thibaut; Budina-Kolomets, Anna; Basu, Subhasree et al. (2018) Tailoring Chemotherapy for the African-Centric S47 Variant of TP53. Cancer Res 78:5694-5705
Plikus, Maksim V; Guerrero-Juarez, Christian F; Ito, Mayumi et al. (2017) Regeneration of fat cells from myofibroblasts during wound healing. Science 355:748-752
Juliana, Christine A; Yang, Juxiang; Rozo, Andrea V et al. (2017) ATF5 regulates ?-cell survival during stress. Proc Natl Acad Sci U S A 114:1341-1346
Ediger, Benjamin N; Lim, Hee-Woong; Juliana, Christine et al. (2017) LIM domain-binding 1 maintains the terminally differentiated state of pancreatic ? cells. J Clin Invest 127:215-229
Jang, Jessica C; Li, Jiang; Gambini, Luca et al. (2017) Human resistin protects against endotoxic shock by blocking LPS-TLR4 interaction. Proc Natl Acad Sci U S A 114:E10399-E10408
Carr, Rotonya M; Dhir, Ravindra; Mahadev, Kalyankar et al. (2017) Perilipin Staining Distinguishes Between Steatosis and Nonalcoholic Steatohepatitis in Adults and Children. Clin Gastroenterol Hepatol 15:145-147
Park, Hyeong Kyu; Kwak, Mi Kyung; Kim, Hye Jeong et al. (2017) Linking resistin, inflammation, and cardiometabolic diseases. Korean J Intern Med 32:239-247
Ackermann, Amanda M; Zhang, Jia; Heller, Aryel et al. (2017) High-fidelity Glucagon-CreER mouse line generated by CRISPR-Cas9 assisted gene targeting. Mol Metab 6:236-244

Showing the most recent 10 out of 220 publications