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

概述：本区域项目的目标是绘制一个对血管内皮生长因子（VEGF）表达有重大影响的基因。在前期雌激素诱导垂体肿瘤生长数量性状位点的绘制中，我发现大鼠5号染色体（Chr 5）上有一个遗传因子对雌激素诱导的VEGF表达有较大影响。出于本建议的目的，我将此遗传因子称为SEV（雌激素诱导VEGF表达的抑制因子）。当大鼠具有来自F344大鼠株的SEV等位基因时，雌激素处理诱导所有细胞类型中VEGF蛋白的高水平表达。相比之下，当大鼠具有BN株SEV等位基因时，雌激素处理后VEGF蛋白没有增加。因此，尽管受到雌激素的持续刺激，SEV的BN等位基因仍赋予组织具有控制VEGF水平的能力。目前已知SEV位于大鼠Chr 5上，但其位置尚未确定，只知道它位于65 cM的间隔内（因此估计为125 Mb）。在我开始研究SEV基因的作用机制之前，我必须更清楚地从遗传学上定义它。该AREA项目的成功完成将为今后SEV基因的克隆及其作用机制的研究奠定基础。

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.