TSH Hypersecretion in WKY: Positional Candidate Analysis

点击翻译按钮获取中文摘要

DESCRIPTION (provided by applicant): The high comorbidity between hypo- and hyperthyroidism and depressive disorders illustrates the influence of hypothalamic-pituitary-thyroid (HPT) axis function on behavior. The inbred Wistar-Kyoto (WKY) rat strain has persistently elevated TSH despite elevated thyroid hormone levels and normal negative feedback to the pituitary. Also, WKY are hypoactive in a variety of behavioral tests, including the open-field test. The strain is thus an excellent model for dissecting the relationships between multigenic behavioral traits and complex hormonal control systems using forward genetics. Genetic architectures of these traits will be investigated with quantitative trait locus (QTL) analysis. An F2 intercross population has been created from reciprocal crosses between WKY and the genetically, hormonally and behaviorally polymorphic Fischer-344 strain. The WKYxF344 F2 generation is sufficient to segregate phenotypic traits and create a linkage map to perform a QTL analysis. By demonstrating an association between an extreme expression of these phenotypes and marker alleles whose genetic map position is known, loci will be mapped to specific regions of individual chromosomes, and commonalities between the behavioral and hormonal traits? genetic architectures will be revealed. Significant loci of interest will be introgressed into congenic strains using marker-and phenotype-assisted selection, which will confirm the locus? role in the phenotype and permit its further analysis in isolation from other segregating loci that may modify its expression. The loci will also be analyzed using a positional candidate approach utilizing homology maps linking rat, mouse and human genomes. These experiments will contribute to the understanding of HPT regulation, and also illuminate any genetic links that may exist between these phenotypes.