1. The mechanism of pancreatic beta cell replication

We are interested in studying gene networks and signaling pathways that control pancreatic beta cell replication under insulin resistance. The laboratory set up an acute insulin resistance mouse model by infusion of an insulin receptor antagonist, S961, which induces dramatic and specific pancreatic beta-cell replication. Our major focus is using this model to search for novel factors, secreted proteins and hormones from various organs/tissues, as well as beta-cell genes that control pancreatic beta-cell proliferation. We also use this model to study cross-organ communication that regulates beta cell functions.

2. The mechanism of pancreatic beta cell neogenesis from pancreatic duct cells

Pancreatic beta cells can be trans-differentiated from other cell types, such as pancreatic duct cells (beta cell neogenesis from duct cells). Many evidences suggest that pancreatic duct cells have the potential to serve as beta cell progenitor cells under certain conditions, but the underlying mechanism is poorly understood. Our laboratory uses genome-wide CRISPR screen trying to identify novel genes and signal pathways that control the trans-differentiation of pancreatic duct cells into beta or beta-like cells.

3. Genetic protection of pancreatic beta-cells against autoimmune destruction in Type 1 Diabetes

The laboratory is using whole-genome gain-of-function and loss-of-function in vivo CRISPR screens to investigate the mechanism of pancreatic beta-cell tolerance and vulnerability in Type 1 Diabetes. We recently discovered 11 novel genes, the mutation of which can render beta-cells resistant to autoimmune killing.  We currently focus on the study of one of these genes, RNLS, a Type 1 Diabetes GWAS gene. We also identified an FDA approved drug, pargyline, that is able to target RNLS and protect pancreatic beta cells in Type 1 Diabetes mouse model.

4. Genome-wide CRISPR screens to study various questions in beta cell biology

The laboratory is applying a genome-wide CRISPR screen technique to investigate various questions in beta cell biology, including beta-cell stress, function, allotransplantation tolerance, as well as human beta-cell proliferation.

(1). Cai EP, Ishikawa Y, Zhang W, Leite NC, Li J, Hou S, Kiaf B, Hollister-Lock J, Yilmaz NK, Schiffer CA, Melton DA, Kissler S, Yi P. Genome-scale in vivo CRISPR screen identifies RNLS  as a target for beta cell protection in type 1 diabetes.  Nature Metabolism. 2020 Sep;2(9):934-945, PMID: 32719542

(2). Shirakawa J, Fernandez M, Takatani T, El Ouaamari A, Jungtrakoon P, Okawa ER, Zhang W, Yi P, Doria A, Kulkarni RN. Insulin Signaling Regulates the FoxM1/PLK1/CENP-A Pathway to Promote Adaptive Pancreatic Beta Cell Proliferation. Cell Metab. 2017 Apr 4;25(4):868-882.e5. PMID: 28286049

(3). Cox AR, Barrandon O, Cai EP, Rios JS, Chavez J, Bonnyman CW, Lam CJ, Yi P, Melton DA, Kushner JA. Resolving Discrepant Findings on ANGPTL8 in β-Cell Proliferation: A Collaborative Approach to Resolving the Betatrophin Controversy.  PLOS One. 2016, Jul 13;11(7): e0159276.  doi: 10.1371/journal.pone.0159276.  eCollection 2016. PMID: 27410263    

(4). Yi P, Johnson A, Han Z, Wu J, Li X, Olson EN. Heterotrimeric G proteins regulate a non-canonical function of septate junction proteins to maintain cardiac integrity in Drosophila. Dev Cell, 2008, Nov 11;15(5): 704-713. PMID: 19000835

(5). Yi P, Han Z, Li X, and Olson EN. The Mevalonate Pathway Controls Heart Formation in Drosophila by Isoprenylation of G{gamma}1. Science, 2006 Sep 1;313(5791):1301-3. Epub 2006 Jul 20. PMID: 16857902

(6).  Han Z, Yi P, Li X, Olson EN. Hand, an evolutionarily conserved bHLH transcription factor required for Drosophila cardiogenesis and hematopoiesis. Development. 2006 Mar; 133(6): 1175-82. PMID: 16467358   

(7).  Miao L, Yi P, Wang Y, Wu M.  Etoposide upregulates Bax-enhancing tumour necrosis factor-related apoptosis inducing ligand-mediated apoptosis in the human hepatocellular carcinoma cell line QGY-7703. Eur J Biochem. 2003 Jul; 270(13): 2721-31. PMID: 12823542      

(8). Yi P, Zhang W, Zhai Z, Miao L, Wang Y, Wu M.  Bcl-rambo beta, a special splicing variant with an insertion of an Alu-like cassette, promotes etoposide- and Taxol-induced cell death. FEBS Lett. 2003 Jan 16; 534(1-3): 61-8. PMID: 12527362