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David W Threadgill, PhD
Associate Professor

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Research Interests

Our laboratory is broadly interested in elucidating the genetics of individuality. We are particularly interested in the identification and functional characterization of genes influencing an individual's innate susceptibility to various diseases, in the interaction between genes and the environment, and in the biological role of the Erbb gene family. Although mouse genetics is our predominant research tool, we are also actively using complementary molecular and proteomic tools. The approach we are taking to study indiviudal variation is through the integration of genetic, biologic, and engineering tools. Genetics permits the detection and regional mapping of target genes. Concurrently, we are gathering detailed molecular and proteomic data about the biological variation. These studies will provide valuable insights that will help in the identification of target genes. Lastly, we are also experimenting with a new methods to genetically engineer mice for the eventual validation of candidate genes. Representative projects ongoing in our lab include:

Modifiers of susceptibility to colorectal cancer (CRC). In western societies, Familial Adenomatous Polyposis (FAP) accounts for around 2% of CRC while Hereditary Non-Polyposis Colorectal Cancer (HNPCC) accounts for around 4%. The vast majority of the remaining cases of CRC arise sporadically in individuals thought to have an environmentally - influenced genetic predetermined susceptibility. The discovery that azoxymethane (AOM) is a potent and specific colorectal carcinogen in rodents paved the way for experimental studies on the initiation and progression of sporadic CRC. Using the AOM model, we have begun a series of experiments to address the mode by which resistance/susceptibility to sporadic CRC is determined and to identify the genes that are involved in the process. In our initial screen for variation, we have found strains that differ widely in a number of parameters. In order to simplify mapping of CRC modifiers, we are partitioning the phenotypes.

Gene-environment interactions in gastrointestinal (GI) biology. The GI system also offers many interesting and advantageous features; the GI tract contains a continually proliferating epithelial layer, its development is dependent upon epithelial-mesenchymal interactions, the epithelium follows a distinct differentiation pathway along the crypt-villus axis, it is home to a plethora of bacterial species, and diseases of the GI tract display significant gene-environment interactions. One of our long-term research goals is to study how various environmental factors, particularly diet, interact with the gut flora and specific genetic loci to influence GI disease susceptibility. Similar to the approaches we are taking for CRC modifiers, the innate genetic variability between mouse strains can also be used to identify CRC susceptibility genes that are modulated by diet. Furthermore, we are making use of the germ-free/gnotobiotic facility at UNC to study the role of gut flora on GI biology.

Genetic dissection of Erbb function. The Erbb family of receptor-tyrosine kinases consists of four members, Egfr, Erbb2 (Neu), Erbb3, and Erbb4. These receptors, either through homodimeric or heterodimeric complexes, have been implicated as being involved during multiple stages of tumorigenesis and at many stages of embryonic development. Significant in vitro data exists on their structure-function relationships but scant in vivo testing, other than targeted null alleles, has been performed. Homozygosity for null alleles in these genes produces embryonic or early post-natal death, often dependent on genetic background. Using genetic engineering techniques, we are dissecting the developmental and tumorigenic role of these genes. Furthermore,classical genetic approaches and new molecular profiling technologies are being used to study and identify loci that modify the resulting phenotypes.

Egfr in placental development and intrauterine growth restriction (IUGR). Homozygosity for an Egfr null allele shows a strong genetic background dependency on the resulting phenotype. The major abnormality is disruption of normal placentation reminiscent of IUGR in humans. We are using genetic and genomic approaches to study the mechanism and allelic differences underlying this genetic background-dependent phenotype.

Individual variation in gene expression profiles. Microarrays have become a dominant technology to study alterations in gene expression profiles. We are adapting this technology to study differences related to genetic background. Our current projects are aimed at analyzing gene expression variation in response to toxicants commonly used as chemotherapeutics, analyzing variation in gene expression in the brain associated with differences in behavioral characteristics, and combining with genetic segregation with variation in gene expression to develop gene interaction maps.


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Publications

Threadgill, DW, and Womack, JE. 1988. Regional localization of mouse Abl and Mos proto-oncogenes by in situ hybridization. Genomics 3:82-86.

Threadgill, DW, Fries, R, Faber, LK, Vassart, G, Gunawardana, A, Stranzinger, G, and Womack, JE. 1990. The thyroglobulin gene is syntenic with the MYC and MOS proto-oncogenes and carbonic anhydrase II and maps to chromosome 14 in cattle. Cytogenetics Cell Genetics 53: 32-36.

Threadgill, DW, Wilkemeyer, M, Womack, JE, and Ledley, FD. 1990. Localization of the murine methylmalonyl CoA mutase (Mut) locus on chromosome 17 by in situ hybridization. Cytogenetics Cell Genetics 53: 112-114.

Threadgill, DW, and Womack, JE. 1990. Syntenic conservation between humans and cattle I: human chromosome 9. Genomics 8:22-28.

Threadgill, DW, Adkison, LR, and Womack, JE. 1990. Syntenic conservation between humans and cattle II: human chromosome 12. Genomics 8:29-34.

Threadgill, DW, and Womack, JE. 1990. Genomic analysis of the major bovine milk protein genes. Nucleic Acids Research 18:6935-6942.

Threadgill, DW, and Womack, JE. 1991. Synteny mapping of human chromosome 8 loci in cattle. Animal Genetics 22:117-122.

Gallagher, DS, Threadgill, DW, Jackson, AP, Parham, P, and Womack, JE. 1991. Somatic cell mapping of bovine clathrin light chain genes: identification of a new bovine syntenic group. Cytogenetics Cell Genetics 56:154-156.

Fries, R, Threadgill, DW, Hediger, R, Gunawardana, A, Blessing, M, Jorcano, JL, Stranzinger, G, and Womack, JE. 1991. Mapping of bovine cytokeratin sequences to four different sites on three chromosomes. Cytogenetics Cell Genetics 57:135-141.

Georges, M, Gunawardana, A, Threadgill, DW, Lathrop, M, Olsaker, I, Mishra, A, Sargeant, L, Schoeberlein, A, Steele, M, Terry, C, Threadgill, DS, Zhao, X, Holm, T, Fries, R, and Womack, JE. 1991. Characterization of a set of variable number of tandem repeat markers conserved in Bovidae. Genomics 11:24-32.

Bishop, MD, Tavakkol, A, Threadgill, DW, Simmen, FA, Simmen, RCM, Davis, ME, and Womack, JE. 1991. Somatic cell mapping and restriction fragment length polymorphism analysis of bovine insulin-like growth factor 1 (IGF1). Journal of Animal Science 69:4306-4311.

Dietz, AB, Georges, M, Threadgill, DW, Womack, JE, and Schuler, LA. 1992. Somatic cell mapping, polymorphism, and linkage analysis of bovine prolactin-related proteins and placental lactogen. Genomics 14:137-143.

Nan, Z, Threadgill, DW, and Womack, JE. 1992. Synteny mapping in the bovine: genes from human chromosome 4. Genomics 14:131-136.

Sharan, SK, Holdener-Kenny, B, Threadgill, DW, and Magunson, T. 1992. Genomic mapping within the albino-deletion complex using individual early postimplantation mouse embryos. Mammalian Genome 3:79-83.

Gallagher, DS, Threadgill, DW, Ryan, AM, Womack, JE, and Irwin, DM. 1993. Physical mapping of the lysozyme gene family in cattle. Mammalian Genome 4:368-373.

Threadgill, DS, Threadgill, DW, Moll, YD, Weiss, JA, Zhang, N, Davey, HW, Wildeman, AG, and Womack, JE. 1994. Syntenic assignment of human chromosome 1 homologous loci in the bovine. Genomics 22:626-630.

Threadgill, DW, Dlugosz, AA, Hansen, L, Tennenbaum, T, Lichti, U, Yee, D, LeMantia, C, Mourton, T, Herrup, K, Harris, RC, Barnard, JA, Yuspa, SH, Coffey, RJ, and Magnuson, T. 1995. Targeted disruption of mouse EGF-receptor: effect of genetic background on mutant phenotype. Science 269:230-234.

Denning, MF, Dlugosz, AA, Threadgill, DW, Magnuson, T, and Yuspa, SH. 1996. Activation of the epidermal growth factor receptor signal transduction pathway stimulates tyrosine phosphorylation of protein kinase Cd. Journal of Biological Chemistry 271:5325-5331.

Tong, BJ, Das, SK, Threadgill, DW, Magnuson, T, and Dey, SK. 1996. Differential expression of the full-length and truncated forms of the epidermal growth factor receptor in the preimplantation mouse uterus and blastocyst. Endocrinology 137:1492-1496.

Hansen, LA, Alexander, N, Hogan, ME, Sundberg, JP, Dlugosz, A,Threadgill, DW, Magnuson, T, and Yuspa, SH. 1997. Genetically null mice reveal a central role for epidermal growth factor receptor in the maturation of the hair follicle and normal hair development. American Journal of Pathology 150:1959-1975

Threadgill, DW, Yee, D, Matin, A, Nadeau, JH, and Magnuson, T. 1997. Genealogy of the 129 inbred strains: 129/SvJ is a contaminated inbred strain. Mammalian Genome 8:390-393.

Threadgill, DW, Matin, A, Yee, D, Carrasquillo, MM, Henry, KR, Rollins, KG, Nadeau, JH, and Magnuson, T. 1997. SSLPs to map genetic differences between the 129 inbred strains and closed-colony random bred CD-1 mice. Mammalian Genome 8:441-442.

Dlugosz, AA, Hansen, L, Cheng, C, Alexander, N, Denning, MF, Threadgill, DW, Magnuson, T, Coffey, RJ, Yuspa, SH. 1997. Targeted disruption of the epidermal growth factor receptor impairs growth of squamous papillomas expressing the v-ras (Ha) oncogene but does not block in vitro keratinocyte responses to oncogenic ras. Cancer Research 57:3180-3188.

Nishimura, H, Yerkes, E, Hohenfellner, K, Miyazaki, Y, Ma, J, Hunley, TE, Yoshida, H, Ichiki, T, Threadgill, D, Phillips, JA 3rd, Hogan, BM, Fogo, A, Brock, JW 3rd, Inagami, T, Ichikawa, I. 1999. Role of the angiotensin type 2 receptor gene in congenital anomalies of the kidney and urinary tract, CAKUT, of mice and men. Molecular Cell 3:1-10.

Denning, MF, Dlugosz, AA, Cheng, C, Dempsey, PJ, Coffey, RJ, Threadgill, DW, Magnuson, T, Yuspa, SH. 2000. Cross-talk between epidermal growth factor receptor and protein kinase C during calcium-induced differentiation of keratinocytes. Experimental Dermatology 9:192-199.

Reiter, JL, Threadgill, DW, Eley, GD, Strunk, KE, Danielsen, AJ, Schell-Sinclair, C, Pearsall, RS, Green, PJ, Yee, D, Lampland, AL, Balasubramaniam, S, Crossley, TO, Magnuson, TR, James, CD, Maihle, NJ. 2001. Comparative genomic sequence analysis and isolation of human and mouse alternative Egfr transcripts encoding truncated receptor isoforms. Genomics 71:1-20.

Chaurand, P, DaGue, BB, Pearsall, RS, Threadgill, DW, Caprioli, RM. 2001. Profiling proteins from azoxymethane-induced colon tumors at the molecular level by MALDI mass spectormetry. Proteomics 1:1320-1326.

Roberts, RB, Min, L, Washington, MK, Olsen, SJ, Settle, S, Coffey, RJ, Threadgill, DW. 2002. The epidermal growth factor receptor is required for establishement of intestinal tumors in the ApcMin mouse model. Proceedings of the National Academy of Science USA 99:1521-1526.

Threadgill, DW, Lu, L, Airey, D, Manly, K, Williams, RW. Extending the utility of recombinant inbred strains through recombinant inbred intercrosses (RIX). Submitted.


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Trainees

Post-Doctoral Fellows

1998-2000: Scott Pearsall (PhD, 1998, Roswell Park Cancer Institute)-Scientist, Hypnion, Inc.

1998 - Present: Daekee Lee (PhD, 1993, Seoul National University)

2001 - Present: Deloris Alexander (PhD, 2001, Meharry Medical College)

2003- Present: Haider Ali Syed

PhD Students

1997 - Present: Karen Strunk, CBIO (1993, BA, Biology, Lehigh University)

1998 - Present: Reade Roberts, CBIO (1997, BS, Biocehmistry, Susquehanna University)

1999 - Present: Lee, Tang-Cheng GMB (1994, MS, Biochemistry, National Taiwan University)

2000 - Present: Anika Bissahoyo, TOX (1998, BS, Biochemistry, University of Maryland)

2003-Present: Delia Barrick

Undergraduate Students


1997 (summer): Vicky Wilkinson (Cambridge University, UK)

2000-2002: Robert Boykin (University of North Carolina, Biology, BS, 2002)-Medical School

2000-present: Ben Wood (University of North Carolina, Biology)

2001-present: Meggan Hovick (University of North Carolina, Biology)

2001-present: Candice Bailey (University of North Carolina, Chemistry)

2001-present: Hal Wray (University of North Carolina, Biology)

2002-present: Rusty Mankinen (University of North Carolina, Biology)

High School Students

1998 (summer): Brandon Schecter (Montgomery Bell Academy, Nashville, TN)

2000/01 (academic year): Elana Adamo (NC School of Math and Science, Durham, NC)


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Contact Information

4340C Medical Biomolecular Research Building, CB 7264
Chapel Hill, NC 27599-7264

Office: 919.843.6472
Lab: 919.843.6470
Fax: 919.966-3015

Website: http://www.mouselab.org
Email: dwt<at>med.unc.edu


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