Weidong Wang, PhD
Assistant Professor of Medicine
941 Stanton L. Young Blvd.,
Lab - BSEB 316
Oklahoma City, OK 73104
office ext 48497
lab ext 44927
Pancreatic β-cell death and dysfunction plays essential roles in the development of both type 1 and 2 diabetes. On the other hand, β-cells have a huge capacity to regenerate to meet metabolic demands. Hence, the ability to restore and maintain functional β-cell mass via β-cell regeneration/transplantation and survival will provide the means to treat or even cure diabetes.
1. Induction of β-cell regeneration:
β-cells have a huge capacity to regenerate to meet metabolic demands during pregnancy or obesity primarily via replication of preexisting β cells, although the exact molecular mechanisms of β-cell regeneration remain poorly understood. Our research on β-cell regeneration is two-pronged: identification of molecules that increase the replication of functional β-cells and elucidation of mechanisms of β-cell regeneration during pregnancy or obesity. We have recently identified small molecules and growth factors that promote beta cell regeneration both in vitro and in vivo using high throughput screening (HTS) technology and some are capable of reversing hyperglycemia in diabetic animals by restoring β-cell mass. In addition, to understand the mechanisms by which β-cells regenerate during pregnancy, we have utilized next-generation sequencing technology to successfully identify a number of miRNAs that are differentially expressed in β-cells between pregnancy or obesity and control animals. We are currently investigating the roles of some miRNAs in β-cell regeneration and/or development in inducible transgenic and conditional knockout mouse models. Although at its infantry, research on β-cell regeneration may provide an effective treatment or even a cure for diabetes, and understanding the molecular mechanisms underlining the process could identify therapeutic targets for developing novel approaches to increase β-cell mass.
2. Induced pluripotent stem cell (iPSC) differentiation and β cell
Transplantation of islet β-cells using the Edmonton protocol has been shown to successfully normalize blood glucose levels. However, the limited availability of donor islets prevents its broad application. To overcome this hurdle, we strive to develop efficient iPSC differentiation protocol to convert iPSCs to high-quality mature β cells for transplantation. With Crispr-CAS9 technology, our work aims at defining and characterizing late stage progenitors of β 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.
3. β-cell survival and endoplasmic reticulum (ER) stress
The ER stress has been proposed to be a major mechanism for β cell dysfunction and death in diabetes. ER stress activates the unfolded protein response (UPR) through three signaling branches (IRE1, PERK and ATF6). The UPR initially alleviates the ER stress but leads to apoptosis via the activation of deleterious UPR genes (such as CHOP and TXNIP) if the ER stress is severe or prolonged. Using HTS technology, we have identified small molecules that protect β cells from ER stress-induced death, the first of such efforts using β cells. These small molecules will be utilized to dissect the molecular and cellular mechanisms underlying the switch between β-cell survival and apoptosis under ER stress, and to serve as leads in the development of therapeutic interventions for diabetes treatment.
Combining stem cell/regeneration, chemical biology approach, ER stress, and miRNA biology with cell-based and animal models of β-cell biology, we aim to uncover mechanisms of β-cell differentiation, regeneration, and survival during normal and diseased conditions and discover and develop chemical and biological therapeutic agents for the treatment of diabetes.
||PhD - Columbia University, New York
||MPhil - Columbia University, New York
||MA - Columbia University, New York
||MSc - Fudan University Medical Center, China
Duan H, Lee JW*, Moon SW, Arora D, Lim H-Y, and Wang W*. Discovery, Synthesis and Evaluation of 2,4-diaminoquinazolines as a Novel Class of Pancreatic β Cell-Protective Agents against ER Stress. Journal of Medicinal Chemistry. 2016. DOI:10.1021/acs. jmedchem.6b00041.
Lee, SJ., Bao, H., Ishikawa, Z., Wang, W*., and Lim, H-Y*. Cardiomyocyte regulation of systemic lipid metabolism by the apolipoprotein B-containing lipoproteins in Drosophila. Under Revision.
Duan H, Arora DK, Li Y, Setiadi H, Xu D, Lim H-Y, and Wang W*. Identification of 1,2,3-triazole derivatives that protect β cells against endoplasmic reticulum stress by inhibiting expression of C/EBP-homologous protein. Bioorganic and Medicinal Chemistry. 2016 Jun 15;24(12):2621-30. doi: 10.1016/j.bmc.2016.03.057.
Duan H, Li Y, Lim H-Y, and Wang W*. Identification of a 5-nitrofuran-2-amide derivative as inducer of triple-negative breast cancer cell apoptosis by activating the C/EBP-homologous protein CHOP expression. Bioorganic and Medicinal Chemistry. 2015 Aug 1;23(15):4514-21. doi: 10.1016/j.bmc.2015.06.011.
Tran KM, Li Y, Duan H, Arora DK, Lim H-Y, and Wang W*. Identification of small molecules that protect pancreatic β cells against ER stress-induced cell death. ACS Chemical Biology. 2014, 9(12):2796-806. DOI: 10.1021/cb500740d.
Lim H-Y, Wang W, Chen J, Ocorr K, Bodmer R. ROS regulate cardiac function in Drosophila via a novel paracrine mechanism. Cell Reports. 2014, 7(1):35-44. doi:10.1016/j.celrep.2014.02.029.
Shen W, Tremblay MS, Deshmukh VA, Wang W, Filippi CM, Harb G, Zhang YQ, Kamireddy A, Baaten JE, Jin Q, Wu T, Swoboda JG, Cho CY, Li J, Laffitte BA, McNamara P, Glynne R, Wu X, Herman AE, Schultz PG. Small-molecule inducer of β cell proliferation identified by high-throughput screening. Journal of American Chemistry Society. 2013, 135(5), pp 1669–1672.
Lim H-Y, Wang W, Wessells RJ, Ocorr K, and Bodmer R. Phospholipid homeostasis regulates lipid metabolism and cardiac function through SREBP signaling in Drosophila. Genes & Development. 2011. 25(2):189-200. PMCID: PMC3022264
Wang W, Walker JR, Wang X, Tremblay MS, Lee JW, Wu X, and Schultz PG.Identification of small-molecule inducers of pancreatic β-cell expansion. Proceedings of the National Academy of Sciences, USA. 2009, 106(5):1427-32.
Wang W and Struhl G. Distinct roles for Mind bomb, Neuralized and Epsin in mediating DSL endocytosis and signaling in Drosophila. Development. 2005, 132, 2883-2894.
Wang W and Struhl G. Drosophila Epsin mediates a select endocytic pathway that DSL ligands must enter to activate Notch. Development. 2004, 131, 5367-5380.