Pei Wang, Ph.D.Assistant Professor
Baylor College of Medicine, 2004
Dr. Pei Wang received her Ph.D from Baylor College of Medicine where she studied the developmental functions of Alzheimer's disease genes. Then she joined Dr. Seung Kim's laboratory at Stanford University School of Medicine and Howard Hughes Medical Institute for her postdoctoral training where she focused on genetic manipulation of human embryonic stem cells to study endoderm development. Dr. Wang joined the Department of Cellular and Structural Biology in September of 2012; she received a Texas Rising STAR award and a first time tenure track faculty award from the Cancer Prevention and Research Institute of Texas (CPRIT).
The lab is focused on the two major diseases of the pancreas: diabetes which involves the endocrine tissue and PDAC (pancreatic ductal adenocarcinoma), a cancer of the exocrine pancreas that is notorious for its dismal prognosis. The current proposal describes an innovative approach to develop a novel model of human PDAC that will allow the lab to dissect the underlying mechanisms of tumorigenesis in this devestating disease.
A combination of earlier diagnosis and improved treatments in the past thirty years has notably increased the 5-year survival rates for many cancers. However, survival rate for pancreatic adenocarcinoma has not been improved and remains one of the lowest. This has been attributed to the lack of early detection and/or effective treatments. Our major focuses are to identify early markers for diagnosis and to understand disease pathogenesis for use in developing effective therapies. With our expertise in genetic manipulation, we will recapitulate the PDAC pathogenesis using the unique culture system for normal human pancreatic tissue. Mutations in the KRAS gene are one of the earliest and most frequent (>95%) alterations seen in PDAC. Thus, we are expressing mutant KRAS, in normal pancreatic cells to mimic initiation of disease. Further, we are building a set of novel genome editing tools to inactivate tumor suppressor genes in a controlled temporal and sequential manner to provide insight into disease progression. In addition, we are using mouse genetic methods to study the involvement of the Hippo pathway, a central regulator of organ size, cell polarization, and apoptosis, in PDAC tumorigenesis. The immediate goals for our research are:
- to generate genetically engineered human pancreatic cells to model PDAC,
- to identify signals that will promote engineered human pancreatic cells to proliferate and undergo epithelial to mesenchymal cell transition, and
- to understand the mechanistic role of KRAS in PDAC initiation and progression, and specifically, the involvement of the hippo pathway.
The other interest of my lab is to generate insulin producing cells (IPCs) from human embryonic stem cells (hESCs) and induced pluripotent stem cells (iPSC) for modeling disease and for cell replacement therapies for diabetes. Significant effort has been made in developing step-wise differentiation protocols to recapitulate the developmental pathways necessary for generation of IPCs in vitro. However, multiple research groups showed that in vitro generated IPCs remain poly-hormonal and do not secrete insulin in response to glucose stimulation; this is characteristic of immature β-cells and therefore would not be useful as a diabetes therapy. Thus, it is vital to develop an iPSC/hESC differentiation method that generates fully differentiated β-cells that produce only insulin and are capable of secreting it upon glucose stimulation. Monitoring insulin secretion is critical for identifying optimal conditions for differentiating iPSCs/hESCs into mature β-cells. Using our expertise in modifying hESCs, we are generating a reporter human ESC line that Insulin secretion can be easily detected. With this genetically modified hESC line, we will perform high-throughput screening of small molecules and culture conditions that will facilitate the maturation of in vitro generated IPCs. The ultimate goal is to develop a method to generate functional insulin producing cells for cell therapy in patients with diabetes.
Human embryonic stem cell (hESC) and induced pluripotent stem cell (iPSC) culture
Gene targeting in hESC and iPSC
Molecular biology technique
Mouse ES cell targeting and growth
Histologic assessment and disease pathogenesis
Wang P, McKnight KD, Wong DJ, Rodriguez RT, Sugiyama T, Gu X, Ghodasara A, Qu K, Chang HY, Kim SK. (2012) A molecular signature for purified definitive endoderm guides differentiation and isolation of endoderm from mouse and human embryonic stem cells. Stem Cells Dev. 2012 Aug 10;21(12):2273-87.
Hung T, Wang Y, Lin MF, Koegel AK, Kotake Y, Grant GD, Horlings HM, Shah N, Umbricht C, Wang P, Wang Y, Kong B, Langerød A, Børresen-Dale AL, Kim SK, van de Vijver M, Sukumar S, Whitfield ML, Kellis M, Xiong Y, Wong DJ, Chang HY. (2011) Extensive and coordinated transcription of noncoding RNAs within cell-cycle promoters. Nat Genet. 2011 Jun 5;43(7):621-9.
Wang P, Rodriguez RT, Wang J, Ghodasara A, Kim SK. (2011) Targeting SOX17 in human embryonic stem cells creates unique strategies for isolating and analyzing developing endoderm. Cell Stem Cell. 2011 Mar 4;8(3):335-46.
Wang P, Yang G, Mosier DR, Chang P, Zaidi T, Gong YD, Zhao NM, Dominguez B, Lee KF, Gan WB, Zheng H. (2005) Defective neuromuscular synapses in mice lacking amyloid precursor protein (APP) and APP-Like protein 2. J Neurosci. 2005 Feb 2;25(5):1219-25.
Wang P, Pereira FA, Beasley D, Zheng H. (2003) Presenilins are required for the formation of comma- and S-shaped bodies during nephrogenesis. Development. 2003 Oct;130(20):5019-29.