Current Projects Index

1. The Collaborative Cross
2. Functional Annotation of Human Chromosomes 5, 16 and 19 Genes with Gene-Driven Mutagenesis in Mice
3. Systems Biology of the Mammalian Cilium
4. Elucidating the Role of the Nell1 gene in Osteoblast and Chrondrocyte Differentiation during Skull and Vertebral Column Development
5. Genetic variation in the health outcome of exposure to low doses of ionizing radiation
6. Interactions between an obesigenic environment and the renin-angiotensin system
7. Health effects of inhaled nanoparticles

Summary of Current Projects

The Collaborative Cross, a community resource for the genetic analysis of complex traits. Nature Genetics, Volume 36.

The Collaborative Cross is a randomized cross of eight inbred mouse strains designed by members of the Complex Trait Consortium. Oak Ridge National Laboratory is the North American site of the collaborative cross, designed to be the ultimate mouse reference population. The cross features a randomized assortment of 8 inbred strains. The lines are first crossed pairwise to make all 56 possible G1 parents. A set of possible 4-way crosses is performed, keeping Y-chromosome and mitochondrial balance. Finally, all 8 genomes are brought together in G3, and the offspring of this cross are inbred. 90% inbreeding is expected at G23 based on theoretical results.

Functional Annotation of Human Chromosomes 5, 16 and 19 Genes with Gene-Driven Mutagenesis in Mice.

We are generating chemically-induced point mutations for genes that are predicted to be important in a variety of biological pathways such as: immune response, behavior (learning, memory and drug dependence), intracellular transport and trafficking of proteins, skeletal development and imprinting. We are targeting selected mouse genes with homologues in human chromosomes 5, 16 and 19 and contain protein domains that are highly conserved across distantly related genomes.

Systems Biology of the Mammalian Cilium: A Cellular Organelle Essential for Human Health and Development.

A Systems Biology approach is being applied to understand cilia function in human health and disease. Mouse mutations for genes that are predicted to be essential in cilia assembly and function are being generated and then phenotyped at the molecular, cellular and whole-animal levels. This project is in collaboration with experts in cilia structure and function at the University of Alabama at Birmingham.

Elucidating the Role of the Nell1 gene in Osteoblast and Chrondrocyte Differentiation during Skull and Vertebral Column Development.

We are currently determining the molecular and cellular mechanisms mediated by Nell1, a protein kinase C beta 1-binding protein that is important in the formation of bone and cartilage during fetal development. Mice with loss-of-function mutations in the Nell1 gene exhibit skeletal defects in the skull, vertebral column and ribcage.

Genetic variation in the health outcome of exposure to low doses of ionizing radiation

The detrimental effects of high doses of radiation are well-known, but the physiological consequences of lower doses are poorly defined. Standard and recombinant inbred strains of mice are used to dissect robust responses to low dose exposures from those that depend on genetic background. Transcriptome profiling is combined with functional responses and pathway mining tools to identify the molecular mechanisms that underlie low dose radiation effects.

Interactions between an obesigenic environment and the renin-angiotensin system.

Adipose tissue produces an increasing repertoire of adipokines with both local and systemic actions. Levels of many of these factors are modulated by diet and energy balance. Mouse models of altered production of one such adipokine, angiotensin II, are used to probe the extent to which adipose tissue directly contributes to conditions that are co-morbid with obesity, such as type II diabetes.

Health effects of inhaled nanoparticles.

Nanoparticles are both manufactured for their own value in a growing range of applications and produced as byproducts of manufacturing processes. Despite their rapidly increasing use, the health effects of inhaled nanoparticles have not been well-characterized. Mouse models are used to explore the potential consequences of exposure to a variety of types of engineered particles of nano scale.