I am currently a postdoctoral fellow in Dr. Klaus Kaestner's laboratory in the Department of Genetics, at University of Pennsylvania. My previous Ph.D. and postdoctoral training experience has been continuously related to gut endoderm development. My immediate goal during the next 3 years is to complete the transition to an independent scientist in the field of gastrointestinal development and diseases. My long-term goal is to investigate the cell polarity regulators and their roles in the gastrointestinal morphogenesis and related diseases. I am working in a very dynamic research environment that has highly interactive scientists from the Department of Genetics, the Gastroenterology Division and the Institute for Diabetes, Obesity and Metabolic Diseases. Dr. Klaus Kaestner will be my primary mentor, and Dr. Anil Rustgi, the Chief of Gastroenterology Division, will be my co-mentor. Dr. Kaestner is an expert in mouse genetics and gut development. Dr. Rustgi is a well-respected expert in gastrointestinal development and diseases. Both mentors have ample experiences in training young scientists and have a track record of successful mentoring and transitioning K awardees into independent faculties. Other key advisors include Dr. Erfei Bi, an expert in Cdc42 and cell polarity research, Dr. Michael Pack, an expert of Zebrafish gut development, and Dr. Hiroshi Nakagawa, an expert in primary tissue culture and organotypic culture model. Two technical consultants, Drs Jonathan Schug and Raymond Meade, will advise me on statistical data analysis and EM experiments. The mammalian intestine contains a highly polarized epithelium that is central to digestion and absorption of nutrients. Although we have ample knowledge about canonical Wnt, Notch and other signaling pathways in the intestinal epithelial morphogenesis, little is known about the roles of key polarity regulators in this process. Several cell polarity genes have been implicated in gastrointestinal diseases, in particular the colon cancer. My recent work with Dr. Kaestner has established Cdx2 as the essential intestinal cell fate director. This work has been accepted by Developmental Cell. Our preliminary data on intestinal epithelium-specific Cdx2 knockout mice suggest that this factor plays an important role in regulating cell polarity formation in differentiated intestinal epithelium, and this effect appears to be associated with the apical Par complex and Cdc42 polarity pathways. Ablation of Cdx2 from differentiated intestinal epithelium leads to a disrupted apical-basolateral cell orientation, an extra tight junction formation, and an impaired basement membrane integrity. We hypothesize that apical polarity complex (Par3/Par6/aPKc/Cdc42) incorporates intestinal cell lineage information to instruct polarity formation during epithelial morphogenesis. We propose to analyze the spatial and temporal activity of Par/aPKC and Cdc42 during normal intestinal polarization, and investigate the molecular mechanism by which Cdx2 regulates apical polarity activation during the morphogenetic process. We will further define the role of Cdc42, a master regulator of cell polarity, in the development of intestine, using a novel intestinal organotypic culture model, in combination with the intestine-specific Cdc42 knockout mouse model. These studies will elucidate the basic mechanisms of cell polarity regulation in mammalian epithelial morphogenesis, and will contribute to a better understanding of related gastrointestinal diseases. The goal of this proposal is directly relevant to the mission of NIDDK. The training process will expand my technical capacities such as the development of a novel intestinal organotypic culture model, and the utilization of immuno-electron microscopic analysis to localize polarity regulators during intestinal morphogenesis. The award will protect my time for generating new genetic models including the intestine-specific Cdc42 knockout mice.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Scientist Development Award - Research & Training (K01)
Project #
5K01DK085194-06
Application #
8611918
Study Section
Diabetes, Endocrinology and Metabolic Diseases B Subcommittee (DDK)
Program Officer
Podskalny, Judith M,
Project Start
2010-03-01
Project End
2015-02-28
Budget Start
2014-03-01
Budget End
2015-02-28
Support Year
6
Fiscal Year
2014
Total Cost
$155,822
Indirect Cost
$11,542
Name
Rutgers University
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
130029205
City
Newark
State
NJ
Country
United States
Zip Code
07102
Feng, Qiang; Gao, Nan (2015) Keeping Wnt signalosome in check by vesicular traffic. J Cell Physiol 230:1170-80
DeGraff, David J; Grabowska, Magdalena M; Case, Tom C et al. (2014) FOXA1 deletion in luminal epithelium causes prostatic hyperplasia and alteration of differentiated phenotype. Lab Invest 94:726-39
Yu, Shiyan; Yehia, Ghassan; Wang, Juanfei et al. (2014) Global ablation of the mouse Rab11a gene impairs early embryogenesis and matrix metalloproteinase secretion. J Biol Chem 289:32030-43
Perekatt, Ansu O; Valdez, Michael J; Davila, Melanie et al. (2014) YY1 is indispensable for Lgr5+ intestinal stem cell renewal. Proc Natl Acad Sci U S A 111:7695-700
Yu, Shiyan; Nie, Yingchao; Knowles, Byron et al. (2014) TLR sorting by Rab11 endosomes maintains intestinal epithelial-microbial homeostasis. EMBO J 33:1882-95
Sakamori, Ryotaro; Yu, Shiyan; Zhang, Xiao et al. (2014) CDC42 inhibition suppresses progression of incipient intestinal tumors. Cancer Res 74:5480-92
Sakamori, Ryotaro; Das, Soumyashree; Yu, Shiyan et al. (2012) Cdc42 and Rab8a are critical for intestinal stem cell division, survival, and differentiation in mice. J Clin Invest 122:1052-65
Gao, Nan; Davuluri, Gangarao; Gong, Weilong et al. (2011) The nuclear pore complex protein Elys is required for genome stability in mouse intestinal epithelial progenitor cells. Gastroenterology 140:1547-55.e10
Gao, Nan; Le Lay, John; Qin, Wei et al. (2010) Foxa1 and Foxa2 maintain the metabolic and secretory features of the mature beta-cell. Mol Endocrinol 24:1594-604
Gao, Nan; Kaestner, Klaus H (2010) Cdx2 regulates endo-lysosomal function and epithelial cell polarity. Genes Dev 24:1295-305

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