About the Mouse Heart, Lung, Blood, and Sleep Disorders (HLBS) Center

 

The goal of the mouse models of Heart, Lung, Blood, and Sleep Disorders Center is to elucidate the genetic and biological factors underlying heart, lung, blood, and sleep diseases through the phenotypic characterization of established inbred mouse strains and the generation of mutations in mice followed by comprehensive phenotypic screening.

The Mouse HLBS Center will enable researchers to link both quantitative trait loci (QTL) and single-gene mutations to gene function and disease and to dissect the genetic variation underlying complex cardiovascular, lung, hematopoietic, and sleep dysfunction. The Center will provide public access to all phenotypic and genotypic data produced, unrestricted distribution of mice, and educational and training opportunities to the scientific community.

The specific aims of the Center are described briefly below:

  • Characterize 40 inbred mouse strains to identify variation in multiple phenotypic domains relevant to heart, lung, blood, and sleep disorders; and carry out crosses between strains that differ in multiple phenotypes to locate the major QTL affecting each phenotype. The phenotypic domains include heart (atherosclerosis, plasma lipids, blood pressure), lung (respiratory rate, tidal volume, methacholine reactivity), blood (blood formation, clotting, thrombosis), and sleep disorders (craniofacial dysmorphologies, rest/activity patterns). The domains also include obesity, a risk factor for both heart disease and sleep disorders.

  • Generate new mutations in C57BL/6J mice using N-ethyl-N-nitrosourea (ENU) as the mutagen and improve existing alternative mutagenesis technologies including mutagenesis of ES cells, mutant detection in mice hemizygous for selected chromosomal deletions, and mutagenesis of strains showing predisposition (i. e., "sensitized") to develop particular phenotypes.

  • Screen mutagenized mice to identify new mutants using an initial high-throughput comprehensive screen of the phenotypic domains listed in Aim 1 and test phenotypic deviants to confirm heritability of the observed trait; characterize new mutants by more extensive and detailed phenotypic analysis and genetic mapping in order to maximize their value to the scientific community.

  • Ensure that all information is made promptly and freely available to the research community, develop and implement MutaJax, a database that will provide access to protocols, experimental data, and information on the availability of mutant mice; submit newly generated data on complex trait analysis to the Mouse Genome Database, and provide phenotype-specific genome maps that show the location of all known QTLs, mutants, and candidate genes for each disease phenotype as a guide for future experimentation; deposit information on newly generated mutant mice in the International Mouse Strain Resources, an existing Web-accessible database providing information on all mouse strains and mutants; and deposit data from inbred strain characterization into the Mouse Phenome Database currently under development at TJL.

  • Provide training and education opportunities through courses and workshops including the successful "Genetic Approaches in Complex Heart, Lung and Blood Diseases" course and by expanding the established TJL Visiting Investigator Program.

  • Distribute pathogen-free mutant mice through the well-established distribution system for JAX mice.

  • Establish an internal program to administer the Center and facilitate interaction with other Programs for Genomic Applications funded by this RFA. The programs led by Dr. Quackenbush of The Institute for Genomic Research and by Dr. Jacob of the Medical College of Wisconsin are already interactive with this program.


 

Program for Genomic Applications (PGA)

Supported by the National Heart, Lung, and Blood Institute (NHLBI) (Grant # HL66611)