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Keith Cheng

TitleProfessor
InstitutionCollege of Medicine
DepartmentPathology
Address500 University Drive Hershey PA 17033
Mailbox: H059
Phone7175315635

 Overview 
 overview
PREFERRED TITLE/ROLE:

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


EDUCATION:

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


NARRATIVE:

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.


 Bibliographic 
 selected publications
Publications listed below are automatically derived from MEDLINE/PubMed and other sources, which might result in incorrect or missing publications. Faculty can login to make corrections and additions.
List All   |   Timeline
  1. Canfield VA, Berg A, Peckins S, Wentzel SM, Ang KC, Oppenheimer S, Cheng KC. Molecular phylogeography of a human autosomal skin color locus under natural selection. G3 (Bethesda). 2013; 3(11):2059-67.
    View in: PubMed
  2. Tsetskhladze ZR, Canfield VA, Ang KC, Wentzel SM, Reid KP, Berg AS, Johnson SL, Kawakami K, Cheng KC. Functional assessment of human coding mutations affecting skin pigmentation using zebrafish. PLoS One. 2012; 7(10):e47398.
    View in: PubMed
  3. Ang KC, Ngu MS, Reid KP, Teh MS, Aida ZS, Koh DX, Berg A, Oppenheimer S, Salleh H, Clyde MM, Md-Zain BM, Canfield VA, Cheng KC. Skin color variation in Orang Asli tribes of Peninsular Malaysia. PLoS One. 2012; 7(8):e42752.
    View in: PubMed
  4. Cheng KC, Xin X, Clark DP, La Riviere P. Whole-animal imaging, gene function, and the Zebrafish Phenome Project. Curr Opin Genet Dev. 2011 Oct; 21(5):620-9.
    View in: PubMed
  5. Cheng KC, Hinton DE, Mattingly CJ, Planchart A. Aquatic models, genomics and chemical risk management. Comp Biochem Physiol C Toxicol Pharmacol. 2012 Jan; 155(1):169-73.
    View in: PubMed
  6. Valenzuela RK, Henderson MS, Walsh MH, Garrison NA, Kelch JT, Cohen-Barak O, Erickson DT, John Meaney F, Bruce Walsh J, Cheng KC, Ito S, Wakamatsu K, Frudakis T, Thomas M, Brilliant MH. Predicting phenotype from genotype: normal pigmentation. J Forensic Sci. 2010 Mar 1; 55(2):315-22.
    View in: PubMed
  7. Zinnanti WJ, Lazovic J, Griffin K, Skvorak KJ, Paul HS, Homanics GE, Bewley MC, Cheng KC, Lanoue KF, Flanagan JM. Dual mechanism of brain injury and novel treatment strategy in maple syrup urine disease. Brain. 2009 Apr; 132(Pt 4):903-18.
    View in: PubMed
  8. Ekker SC, Parichy DM, Cheng KC. Research implications of pigment biology in zebrafish. Zebrafish. 2008 Dec; 5(4):233-5.
    View in: PubMed
  9. Cheng KC. Skin color in fish and humans: impacts on science and society. Zebrafish. 2008 Dec; 5(4):237-42.
    View in: PubMed
  10. Spitsbergen JM, Blazer VS, Bowser PR, Cheng KC, Cooper KR, Cooper TK, Frasca S, Groman DB, Harper CM, Law JM, Marty GD, Smolowitz RM, St Leger J, Wolf DC, Wolf JC. Finfish and aquatic invertebrate pathology resources for now and the future. Comp Biochem Physiol C Toxicol Pharmacol. 2009 Mar; 149(2):249-57.
    View in: PubMed
  11. Cheng KC. Views on four key questions about zebrafish research. Zebrafish. 2008; 5(1):9-24.
    View in: PubMed
  12. Zinnanti WJ, Lazovic J, Housman C, LaNoue K, O'Callaghan JP, Simpson I, Woontner M, Goodman SI, Connor JR, Jacobs RE, Cheng KC. Mechanism of age-dependent susceptibility and novel treatment strategy in glutaric acidemia type I. J Clin Invest. 2007 Nov; 117(11):3258-70.
    View in: PubMed
  13. Norton HL, Kittles RA, Parra E, McKeigue P, Mao X, Cheng K, Canfield VA, Bradley DG, McEvoy B, Shriver MD. Genetic evidence for the convergent evolution of light skin in Europeans and East Asians. Mol Biol Evol. 2007 Mar; 24(3):710-22.
    View in: PubMed
  14. Chi A, Valencia JC, Hu ZZ, Watabe H, Yamaguchi H, Mangini NJ, Huang H, Canfield VA, Cheng KC, Yang F, Abe R, Yamagishi S, Shabanowitz J, Hearing VJ, Wu C, Appella E, Hunt DF. Proteomic and bioinformatic characterization of the biogenesis and function of melanosomes. J Proteome Res. 2006 Nov; 5(11):3135-44.
    View in: PubMed
  15. Moore JL, Rush LM, Breneman C, Mohideen MA, Cheng KC. Zebrafish genomic instability mutants and cancer susceptibility. Genetics. 2006 Oct; 174(2):585-600.
    View in: PubMed
  16. Zinnanti WJ, Lazovic J, Wolpert EB, Antonetti DA, Smith MB, Connor JR, Woontner M, Goodman SI, Cheng KC. New insights for glutaric aciduria type I. Brain. 2006 Aug; 129(Pt 8):e55.
    View in: PubMed
  17. Sabaliauskas NA, Foutz CA, Mest JR, Budgeon LR, Sidor AT, Gershenson JA, Joshi SB, Cheng KC. High-throughput zebrafish histology. Methods. 2006 Jul; 39(3):246-54.
    View in: PubMed
  18. Blasiole B, Canfield VA, Vollrath MA, Huss D, Mohideen MA, Dickman JD, Cheng KC, Fekete DM, Levenson R. Separate Na,K-ATPase genes are required for otolith formation and semicircular canal development in zebrafish. Dev Biol. 2006 Jun 1; 294(1):148-60.
    View in: PubMed
  19. Zinnanti WJ, Lazovic J, Wolpert EB, Antonetti DA, Smith MB, Connor JR, Woontner M, Goodman SI, Cheng KC. A diet-induced mouse model for glutaric aciduria type I. Brain. 2006 Apr; 129(Pt 4):899-910.
    View in: PubMed
  20. Canada BA, Cheng KC, Wang JZ. QCHARM: a novel computational and scientific visualization framework for facilitating discovery and improving diagnostic reliability in medicine. AMIA Annu Symp Proc. 2006; 870.
    View in: PubMed
  21. Lamason RL, Mohideen MA, Mest JR, Wong AC, Norton HL, Aros MC, Jurynec MJ, Mao X, Humphreville VR, Humbert JE, Sinha S, Moore JL, Jagadeeswaran P, Zhao W, Ning G, Makalowska I, McKeigue PM, O'donnell D, Kittles R, Parra EJ, Mangini NJ, Grunwald DJ, Shriver MD, Canfield VA, Cheng KC. SLC24A5, a putative cation exchanger, affects pigmentation in zebrafish and humans. Science. 2005 Dec 16; 310(5755):1782-6.
    View in: PubMed
  22. Croushore JA, Blasiole B, Riddle RC, Thisse C, Thisse B, Canfield VA, Robertson GP, Cheng KC, Levenson R. Ptena and ptenb genes play distinct roles in zebrafish embryogenesis. Dev Dyn. 2005 Dec; 234(4):911-21.
    View in: PubMed
  23. Duffy KT, McAleer MF, Davidson WR, Kari L, Kari C, Liu CG, Farber SA, Cheng KC, Mest JR, Wickstrom E, Dicker AP, Rodeck U. Coordinate control of cell cycle regulatory genes in zebrafish development tested by cyclin D1 knockdown with morpholino phosphorodiamidates and hydroxyprolyl-phosphono peptide nucleic acids. Nucleic Acids Res. 2005; 33(15):4914-21.
    View in: PubMed
  24. Gerhard GS, Malek RL, Keller E, Murtha J, Cheng KC. Zebrafish, killifish, neither fish, both fish? J Gerontol A Biol Sci Med Sci. 2004 Sep; 59(9):B873-5.
    View in: PubMed
  25. Moore JL, Gestl EE, Cheng KC. Mosaic eyes, genomic instability mutants, and cancer susceptibility. Methods Cell Biol. 2004; 76:555-68.
    View in: PubMed
  26. Cheng KC. A life-span atlas for the zebrafish. Zebrafish. 2004; 1(2):69.
    View in: PubMed
  27. Cheng K. Views on four key questions about zebrafish research. Zebrafish. 2004; 1(2):85-103.
    View in: PubMed
  28. Cheng KC, Levenson R, Robishaw JD. Functional genomic dissection of multimeric protein families in zebrafish. Dev Dyn. 2003 Nov; 228(3):555-67.
    View in: PubMed
  29. Mohideen MA, Beckwith LG, Tsao-Wu GS, Moore JL, Wong AC, Chinoy MR, Cheng KC. Histology-based screen for zebrafish mutants with abnormal cell differentiation. Dev Dyn. 2003 Nov; 228(3):414-23.
    View in: PubMed
  30. Gerhard GS, Cheng KC. A call to fins! Zebrafish as a gerontological model. Aging Cell. 2002 Dec; 1(2):104-11.
    View in: PubMed
  31. Gerhard GS, Kauffman EJ, Wang X, Stewart R, Moore JL, Kasales CJ, Demidenko E, Cheng KC. Life spans and senescent phenotypes in two strains of Zebrafish (Danio rerio). Exp Gerontol. 2002 Aug-Sep; 37(8-9):1055-68.
    View in: PubMed
  32. Moore JL, Aros M, Steudel KG, Cheng KC. Fixation and decalcification of adult zebrafish for histological, immunocytochemical, and genotypic analysis. Biotechniques. 2002 Feb; 32(2):296-8.
    View in: PubMed
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