Genetic mapping of a locus that regulates VEGF expression in a tumor model

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DESCRIPTION (provided by applicant): OVERVIEW: The objective of this AREA project is to map a gene that has a major impact on the expression of vascular endothelial growth factor (VEGF). In previous work to map quantitative trait loci for estrogen-induced pituitary tumor growth, I have found a genetic factor on rat Chromosome 5 (Chr 5) which has a large impact on estrogen-induced VEGF expression. For purposes of this proposal, I will refer to this genetic factor as SEV (suppressor of estrogen induced VEGF expression). When rats have an allele of SEV from the F344 rat strain, estrogen treatment induces a high level of expression of VEGF protein in all cell types. In contrast, when rats have alleles of SEV from the BN strain, there is no increase in VEGF protein after estrogen treatment. Thus, BN alleles of SEV confer the ability of the tissue to have a controlled level of VEGF despite the continued stimulus by estrogen. SEV is currently known to reside on rat Chr 5, but its position has not been defined except that it resides somewhere within an interval of 65 cM (thus an estimated 125 Mb). Before I can begin to study the mechanism by which the proposed SEV gene acts, I must define it more clearly genetically. The successful completion of this AREA project will set the stage for the future cloning of the SEV gene and studies of its mechanism of action. PROJECT AIM: The aim of the AREA project is to localize SEV to an interval of 1 cM (thus an estimated 3 Mb). I will achieve this through genetic mapping using estrogen-induced pituitary VEGF level as the trait to be mapped. The rat strains to be used for mapping are a pair of closely related inbred strains: F344 and F344.BN-Edpm5BN. The F344 strain bears the allele of SEV that corresponds with a high level of VEGF expression after estrogen treatment. F344.BN-Edpm5BN is nearly identical to F344 except that a large (65 cM) segment of rat Chr 5 which includes SEV has been introgressed from the BN strain. PUBLIC HEALTH SIGNIFICANCE: SEV is significant to human health because it has a large controlling effect on VEGF expression. VEGF is a protein signal produced by cells to promote the growth of new blood vessels (angiogenesis), but it is produced at uncontrolled high levels in cancers. The mapping of SEV is the first essential step in the process of discovering how SEV controls VEGF expression.