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Genetic Models of Disease Research Program

Robert J. Barstead, Ph.D. Associate Member, Genetic Models of Disease Research Program G.T. Blankenship Chair in Alzheimer's and Aging Research Adjunct Professor, Department of Cell Biology, University of Oklahoma Health   Sciences Center Director, C. elegans Gene Knockout Project

Research Interests
Since the completion of the genome sequence, it has become clear that traditional forward genetic methods are not sufficient for a comprehensive understanding of all 20,000 of these genes. In response to the limitations of forward genetic methods, my laboratory developed technologies for targeted gene inactivation. Our methods are used worldwide in many individual labs. Although one might leave it up to these individual labs to knockout the function of each of the 20,000 C. elegans genes, four years ago we proposed to the NIH that a systematic, genome-wide gene knockout project, performed by a few labs able to devote the time and resources to the project, would greatly accelerate C. elegans biology and the many biomedical research projects for which C. elegans could provide a model system. This proposal was accepted, and four years ago we formed the C. elegans Gene Knockout Consortium.

It is already clear that our gene knockout resource is immensely valuable to the C. elegans research community. Each strain that we make is deposited in C. elegans Genetics Center where they are accessible to any investigator. Over half of the new strains submitted to the CGC in the last year were from our lab. Further, the CGC filled over 2,000 requests for these strains, accounting for nearly 20 percent of the total strains shipped last year by the CGC. Further, we have numerous examples showing that the resource is especially valuable to those colleagues studying other organisms who wish to exploit C. elegans. Our knockout resource provides a rapid and convenient entry into a model system that allows investigators to bring to bear many unique genetic methods to address significant issues in biomedical and clinical research. By encouraging others to enter the field, especially others who bring the field new experiences and expertise, we accelerate the pace of discovery of protein function in C. elegans and in vertebrates.

Finally, our work allows clinical researchers to exploit C. elegans to study the basic cell biology of several human diseases including polycystic kidney disease, cancer and muscular dystrophy.

Two small molecule drug-like compounds that reduce the function of the mitotic spindle checkpoint in human cells have been shown to have effects on the nematode Caenorhabditis elegans. A better understanding of these compounds may lead to the development of a new class of anti-cancer, chemotherapeutic agents. We are collaborating with Dr. Gary Gorbsky to discover the mechanism of action of these compounds by 1) examining their phenotypic effects on the nematode and 2) through genetic screens to discover putative target genes/pathways that when mutant can render animals resistant to their affects. Using available antibodies and GFP-tagged proteins, first we are characterizing the arrest phenotype induced by these compounds in wild type C. elegans and in animals with mutations in genes with known roles in mitosis or the cell cycle. Second, we have already identified a mutant with a mild chromosome non-disjunction phenotype that is resistant to one of the two compounds described here. We are screening for others which will be mapped genetically and physically to identify the responsible genes and their encoded products. Finally, we have discovered a paradoxical interaction between one of these compounds and the well studied canonical programmed cell death pathway in C. elegans. We are studying the basis for this fascinating interaction to discover the relationship between compound activity and programmed cell death. Understanding this relationship may provide entrées to the development of new therapies that either suppress or activate apoptotic pathways so as to either protect cells from damage or eliminate cells that are diseased.

Joined OMRF Scientific Staff in 1993.

Mailing Address
Genetic Models of Disease Research Program, MS 48
Oklahoma Medical Research Foundation
825 N.E. 13th Street
Oklahoma City, Oklahoma 73104

Contact Information
Phone: (405) 271-1766
Fax: (405) 271-7312
E-mail: Robert-Barstead@omrf.org