David W. Threadgill, PhD

David W. Threadgill, PhD

Adjunct Professor

 

Research Interests


Threadgill David - 1Our 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.

 


Publications:


 


Lab Members

  • Haider Ali
Postdoctoral Fellow ::email
  • David Aylor
Postdoctoral Fellow ::email
  • David Bautz
Postdoctoral Fellow ::email
  • Elyse Lee
Postdoctoral Fellow ::email
  • Christine Powell
Postdoctoral Fellow ::email
  • Jennifer Dackor
Graduate Student ::email
  • Michelle DeSimone
Graduate Student ::email
  • Chevonne Eversley
Graduate Student ::email
  • Erica Rinella
Graduate Student ::email
  • Josh Uronis
Graduate Student ::email
  • Melanie Weed
Graduate Student ::email
  • Yuying Xie
Graduate Student ::email
  • Jill Steigerwalt
Research Assistant ::email

 


Contact Information

Room 5062, Genetic Medicine 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: David W. Threadgill, Ph.D.