Pancreatic islet transplantation provides a promising therapy for Type 1 Diabetes mellitus (Tl DM), in which the majority of pancreatic insulin-producing p-cells are destroyed. The shortage of transplantable donor islets has stimulated much interest in using human pluripotent stem cells such as human embryonic stem cells and human induced pluripotent stem cells (hiPSCs) as alternative, renewable sources to generate functional B-cells. Our long-term goal is to develop an autologous cell-based therapy to replenish insulin producing B-cells for the purpose of treating T1 DM by inducing the differentiation of hiPSCs. The remarkable developmental and differentiation potential of hiPSCs makes them attractive candidates for cell-based therapies. Before the full potential of hiPSCs can be realized, however, it is necessary to understand the complex signaling and genetic mechanisms that control their differentiation. This proposal will employ hiPSC as an exciting new model to dissect the molecular and cellular programs that regulate human B-cells differentiation. Through use of a novel TALEN technology to make knock-in reporter hiPSC lines, the proposed research will develop methods for isolating human B-cells progenitors and tracing the fates of their differentiated progeny. The proposed studies are aimed at defining and characterizing late stage progenitors of B-cell development, establishing their lineage relationships, and identifying cell type-specific cell surface markers of these progenitor populations and signaling pathways that guide their fate. These will be addressed by pursuing three Specific Aims: 1) Develop cell type-specific reporter hiPSCs for ordering events in human B-cells differentiation. 2) Determine the roles of Wnt, Notch and other critical signaling pathways in human B-cells differentiation. 3) Establish the lineage relationships and differentiation potentials of hiPSC derived B-cell sprogenitor subsets. Using genetic, cell biological and in vivo approaches, the planned research will improve our understanding of the molecular and cellular programs underlying human B-cells differentiation, maturation and function.

Public Health Relevance

The proposed studies are broadly aimed at developing novel cell replacement therapies for pancreatic P-cells in order to treat Type 1 Diabetes mellitus (T1DM). These studies will not only allow us to understand the molecular and cellular programs underlying human B-cells development and differentiation but will also provide insights into how to efficiently derive functional human p-cells from stem cells and accelerate efforts to create stem cell based therapies for T1DM.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Exploratory Grants (P20)
Project #
Application #
Study Section
Special Emphasis Panel (ZGM1-TWD-B)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Oklahoma Medical Research Foundation
Oklahoma City
United States
Zip Code
Duan, Hongliang; Arora, Daleep; Li, Yu et al. (2016) Identification of 1,2,3-triazole derivatives that protect pancreatic β cells against endoplasmic reticulum stress-mediated dysfunction and death through the inhibition of C/EBP-homologous protein expression. Bioorg Med Chem 24:2621-30
Borgogno, María V; Monti, Mariela R; Zhao, Weixing et al. (2016) Tolerance of DNA Mismatches in Dmc1 Recombinase-mediated DNA Strand Exchange. J Biol Chem 291:4928-38
Tsou, Pei-Suen; Wren, Jonathan D; Amin, M Asif et al. (2016) Histone Deacetylase 5 Is Overexpressed in Scleroderma Endothelial Cells and Impairs Angiogenesis via Repression of Proangiogenic Factors. Arthritis Rheumatol 68:2975-2985
Griffin, Timothy M; Humphries, Kenneth M; Kinter, Michael et al. (2016) Nutrient sensing and utilization: Getting to the heart of metabolic flexibility. Biochimie 124:74-83
Duan, Hongliang; Lee, Jae Wook; Moon, Sung Won et al. (2016) Discovery, Synthesis, and Evaluation of 2,4-Diaminoquinazolines as a Novel Class of Pancreatic β-Cell-Protective Agents against Endoplasmic Reticulum (ER) Stress. J Med Chem 59:7783-800
Siefert, Joseph C; Clowdus, Emily A; Sansam, Christopher L (2015) Cell cycle control in the early embryonic development of aquatic animal species. Comp Biochem Physiol C Toxicol Pharmacol 178:8-15
Larabee, Chelsea M; Georgescu, Constantin; Wren, Jonathan D et al. (2015) Expression profiling of the ubiquitin conjugating enzyme UbcM2 in murine brain reveals modest age-dependent decreases in specific neurons. BMC Neurosci 16:76
Dozmorov, Mikhail G; Adrianto, Indra; Giles, Cory B et al. (2015) Detrimental effects of duplicate reads and low complexity regions on RNA- and ChIP-seq data. BMC Bioinformatics 16 Suppl 13:S10
Pezza, Roberto J (2015) Mechanisms of chromosome segregation in meiosis--new views on the old problem of aneuploidy. FEBS J 282:2424-5
Lee, Chih-Ying; Horn, Henning F; Stewart, Colin L et al. (2015) Mechanism and regulation of rapid telomere prophase movements in mouse meiotic chromosomes. Cell Rep 11:551-63

Showing the most recent 10 out of 33 publications