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Dr. Geoff Hicks Tel: (204) 787-2133
Fax: 787-2190
Lab: 787-2167 |
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Research Interests: Functional Analysis of the Mammalian Genome. Most mammalian genes will soon be characterized as cDNA sequences and the age of gene discovery will be over. The next major challenge to the Genome Initiative will be to bridge the gap between these rapidly expanding DNA sequence databases and gene function. To utilize the sequence information for large-scale functional studies, we have developed a process called Tagged-Sequence Mutagenesis to disrupt genes expressed in mouse embryo-derived stem (ES) cells and to characterize each mutation by direct DNA sequencing. Comparison of these sequence tags (PSTs) with the existing databases identifies disruptions of known genes or genes which may be related by homology or functional domains. The ability to induce, characterize and maintain mutations in ES cells circumvents many limitations associated with conventional mammalian genetics, and will greatly increase the number of mutant alleles (typically loss of function mutations) by which gene functions can be studied in mice and in cell lines derived from such mice. The process will facilitate a functional analysis of a mammalian genome in vivo and will provide animal models for human genetic diseases. Our initial goal is to develop an Embryonic Stem Cell Library of 20 - 40,000 defined gene mutations. ES cell clones containing specific mutations in genes of interest will be made available to investigators as a national resource. Functional Analysis of TLS, EWS, and ALR in normal development and in oncogenic transformation. Mutations (from the ES cell library) transmitted to the germline will focus on genes known or suspected to be involved in tumor progression. Understanding the normal function of a gene in mammalian development is a powerful approach to understanding how the oncogene contributes to the respective cancer. The focus of the lab is on genes which are translocated in the development of human cancers; specifically, the TLS, EWS and ARL genes. While the translocations and the associated cancers for these genes are highly characterized, little is known about function of the genes themselves or how they contribute to tumor development. Our approach is to analyze developmental defects in mice that are deficient for each specific gene (and are otherwise genetically identical to wild-type mice). For example TLS is a gene that is translocated in many human soft tissue sarcomas and myelogenous leukemia. Functional analysis of mice that are homozygous for the TLS/FUS mutation has revealed TLS plays a critical role in embryogenesis. We are now in a position to examine the function of this gene as it directly relates to the diseased or cancerous state found in humans. Furthermore, we have derived cell lines from the TLS deficient mice that will enable a molecular analysis of the TLS protein, the proteins it interacts with, its regulatory mechanisms, and the signaling pathways it is involved in. Recent Publications:
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