Welcome to PhysGen:

Knock-Out Rats for Physiological Genomics

This project is one of five currently funded Programs for Genomic Applications (PGAs) funded by the National Heart, Lung, and Blood Institute (NHLBI), U01 HL66579.

We are extending our successful PhysGen program by capitalizing on a variety of technological advances, extending our data by manipulating specific genes and assessing the results physiologically in different genetic backgrounds. We aim to test "functionality" of relevant genes by generating knockouts (KO) in rats using a novel strategy that combines ENU mutatgenesis with a TILLING (Targeting Induced Local Lesions in Genomes) assay. TILLING is a general reverse-genetic strategy that provides the ability to detect allelic series of induced point mutations in genes of interest. High-throughput TILLING allows the rapid and low-cost discovery of induced point mutations in populations of chemically mutagenized individuals. As genomic background plays a major role in the expression of phenotypes in mice with KO, we have chosen to make the KOs in the SS (Dahl salt-sensitive; SS/JrHsd/Jr/Mcwi), BN (Brown Norway; BN/Hsd/Mcwi) and FHH (Fawn-Hooded hypertensive; FHH/EurMcwi). We have used these three strains in the development of the two consomic rat panels that were phenotypically characterized during the first five years of this program. This strategy allows us to knock-out genes in disease backgrounds as well as "normal" models, thus narrowing the search for genes in pathways that participate in the disease process.