|Institution||College of Medicine|
|Address||500 University Drive Hershey PA 17033|
Professor of Pathology, Biochemistry and Molecular Biology, and Pharmacology
Chief, Division of Experimental Pathology
Distinguished Professor of Pathology, Biochemistry and Molecular Biology, and Pharmacology
Co-Founding Co-Director of the Penn State IBIOS Bioinformatics and Genomics graduate program (with Cooduvalli Shashikant)
Director, Zebrafish Functional Genomics and Imaging Core
Curator, Zebrafish Atlas
GRADUATE PROGRAM AFFILIATIONS:
Biochemistry and Molecular Biology, Cell and Molecular Biology, Genetics, MD/PhD Degree Program
M.D., New York University School of Medicine, 1980
Ph.D., Fred Hutchinson Cancer Research Center-University of Washington, 1986
Postdoctoral Training, University of Washington, 1987-1992
The Cheng lab is interested in fundamental genetic and molecular mechanisms that cause cancer, basic mechanisms underlying the relationship between human skin pigmentation and cancer, and contributing to web-based infrastructures for science, education, and public service. Our laboratory pioneered genetic screens in zebrafish to find new genes related to cancer. Our screens targeted two processes affected in cancer: mutation and cell differentiation. We are producing an on-line, high-resolution, full-lifespan atlas of the zebrafish that will be integrated with other anatomical web sites of zebrafish, other model organisms, and other disciplines. Collaboratively, we are developing 2D and 3D image informatics tools for systems biology and medicine, and new methods for X-ray based high resolution 3D imaging at cellular and subcellular resolutions. In 2005, we discovered that the putative cation exchanger slc24a5 played a key role in the evolution of light skin in Europeans and modulates vertebrate pigmentation by its effect on melanosome morphogenesis. We are trying to understand why people of East Asian ancestry are not as susceptible to skin cancer as those of European ancestry, by exploring both the molecular mechanisms of melanosome morphogenesis and the genetics underlying the light skin of East Asians/Amerindians.
Answers to the basic question of how and why gene function is lost in somatic tissues will contribute to our understanding of aging and some forms of human disease, including cancer. Those mutations play a key role in the evolution of killer cancer cells from the originally normal ones of cancer victims, and also the evolution of resistant cancer cells after treatment. The tendency to mutate one's DNA can be called genetic instability or genomic instability, and the phenotype of elevated mutation rate is called mutator phenotype. In order to discover new vertebrate genes that control mutation, we have used the zebrafish (Danio rerio) to generate mutants that show elevated rates of somatic (body cell) mutation. In this screen, we scored for increased somatic loss of heterozygosity at a marker locus, golden. We expect genetic instability to be caused by deficiencies in any of a number of functions, including chromosome segregation, recombination, and DNA repair. We are studying the characteristics of mutants, including the ability of the mutations to significantly increase cancer susceptibility, and are engaged in the positional cloning of these mutations. Insights gained from these studies will increase our understanding of the molecular forces that drive evolution and may suggest new ways to fight cancer. Since these genomic instability ("gin") mutants tend to develop cancer, they represent an animal model for human genetic syndromes that predispose to cancer, and may promote the detection of environmental mutagens. This novel approach to the study of genetic instability was sponsored originally by the Jake Gittlen Memorial Golf Tournament, American Cancer Society, and the National Science Foundation.
We are also seeking to increase understanding of cellular differentiation by studying mutants defective in cellular differentiation (dif). These mutants are expected to be affected in any of a variety of functions that may affect cell differentiation, cell cycle regulation, or cell communication (Mohideen et al. 2003). Since these and other experiments require knowledge of the normal gross and microscopic anatomy of the zebrafish, we are now generating a web-based histology and 3D anatomic atlas, currently being executed in collaboration with physicists at University of Chicago and Argonne National Laboratory. This will be the first full life-span atlas of this type (see zfatlas.psu.edu), which will provide a scaffold for gene expression and morphological morphological phenotypic data generated in our laboratory and globally. In recognition of important work being done on specific zebrafish organ systems around the world, we welcome contributions to this effort. We will use scientifically and educationally useful comparisons between stages and organisms. Our goal is to provide a model system atlas with state-of-the-art quality and the most advanced and useful links to related information. Individuals will be able to use images from this resource, as long as permissions are requested and approved by email, and appropriate citations made. Instructions for acknowledgement of the origin of those images will be provided along with permissions. Support for this project has been provided to date by resources of the Jake Gittlen Cancer Research Foundation, and from the National Center for Research Resources at NIH. The results of this work will be integrated with the rich bioinformatics of the community zebrafish site, ZFIN (established by Monte Westerfield and colleagues at the University of Oregon). Plans are underway to expand the project to include comparisons with genetic, reverse genetic, and disease abnormalities, other types of imaging, cross-disciplinary development of new imaging technologies in collaboration with engineers and computer scientists, integration with the web sites of other model systems and disciplines.
We have actively encouraged other laboratories to use the power of zebrafish functional genomics to study the functions of genes in the context of the whole organism, and in development. We have developed the idea that zebrafish functional genomics is a powerful tool for the dissection of the functions of each of the possible combinations of subunit isoforms of multimeric proteins. A detailed discussion of this functional genomics approach, being pursued in collaboration with Drs. Robert Levenson (Na/K ATPase; Department of Pharmacology, Penn State College of Medicine) and Janet Robishaw (heterotrimeric G proteins, Weis Center for Research, Danville, PA) has been recently reviewed (See Cheng, Levenson and Robishaw, 2003, below). We have also participated in Glen Gerhard's pioneering work to define the lifespan of the zebrafish, to set the stage for its use in the study of aging (see publications below with Gerhard, of the Weis Center for Research in Danville).
We are exploring the idea of Systems Morphogenetics, which will yield high-throughput phenotypic profiling as a tool to understand biology and disease. This work, which is currently focused on creating X-ray based micron-scale computed tomographic 3D imaging tools and analysis for whole-animal phenotyping for the zebrafish phenome project, requires a highly collaborative environment that applies cutting edge technologies from computer science, engineering, materials science, bioinformatics, and genetics to the placing of each of these genes in the spatial, temporal, and physiological context of the whole organism. We are building of a team of partners from a broad range of disciplines to create a complete digital map of zebrafish anatomy, microanatomy, and gene expression, in order to create a bioinformatics focused on biological function.
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