The focus of my research program is identification and characterization of genes and genetic networks that influence initiation and progression of cardiovascular disease. To achieve these goals, my research group has developed genetic and genomic tools and methods for nonhuman primate (NHP) research, including large-scale baboon studies in the pedigreed, phenotyped colony at Southwest National Primate Research Center (SNPRC). These essential tools for molecular genetic and genomic studies in baboon allow studies of cardiovascular and other complex diseases.
Research Projects in my Laboratory Include:
Development of NHP Genetic and Genomic Resources - Baboons have been studied for >50 years and are ideal model organisms to study complex human diseases such as hypertension, atherosclerosis, diabetes, and osteoporosis. Our studies are performed on samples from phenotyped, genotyped, pedigreed baboons, allowing targeted selection of discordant animals to analyze complex genetic traits. We constructed a baboon genetic linkage map that is the foundation of genetic variant localization for quantitative traits. In collaboration with Dr. Jeff Wall (University of California at San Francisco), our lab is sequencing 700 baboon genomes from the pedigreed colony. We also created a sequence analysis pipeline using an iterative approach with multiple reference genomes to annotate genome sequences for species without an existing high quality reference genome, or with a poorly annotated reference genome.
Genetic variation that influences risk of cardiovascular disease - We are using baboons discordant for lipoprotein profiles with integrated molecular genetic and genomic approaches to identify genetic variants that influence cardiovascular disease risk. In previous work, we identified a gene splice variant that directly impacts LDL cholesterol serum concentrations. In current studies, we are investigating genetic and epigenetic networks that regulate HDL-cholesterol and LDL-cholesterol.
Discovery of gene variants and mechanisms underlying salt-sensitive hypertension - Our lab is currently using genetic, genomic and bioinformatic approaches to identify polymorphisms and networks that underlie variation in blood pressure response to dietary sodium in baboons. Our long-term goal is to translate these findings to humans for development of new anti-hypertensive therapies.
Establishment of a SPF rhesus macaque colony, MHC typing and genetic characterization core - We genetically manage the colony of the Indian-origin specific pathogen free (SPF) rhesus monkeys for AIDS-related research at SNPRC and are in the process of genetically characterizing the colony by genotyping 219 animals per year using a reduced representation whole genome sequencing approach, genotyping-by-sequencing (GBS).
Genetic and epigenetic responses to the maternal environment - In collaboration with Dr. Peter Nathanielsz (University of Wyoming), we study how the maternal environment influences offspring risk of developing heart disease, diabetes and obesity. Our goal is to identify central genetic and epigenetic networks that underlie offspring response to a sub-optimal intrauterine environment. Central hubs in these networks will provide potential therapeutic targets for disease prevention.
Novel mouse model of obesity in pregnancy - In collaboration with Dr. Thomas Jansson (University of Colorado Anschutz Medical Campus) we are characterizing a new mouse model of obesity in pregnancy, and determine how maternal obesity increases risk of metabolic syndrome in the offspring. We are using RNA-Seq, small RNA-Seq, and bioinformatics tools to identify central molecular networks in fetal tissues, placental tissue and tissues from post-natal offspring that are dysregulated in offspring.
Technologies and Methods:
Illumina RNA-Seq, small RNA-Seq, and exosome RNA-Seq
NGS assembly and annotation pipeline for non-human genomes
Genotyping-by-Sequencing â€“ a reduced representation whole genome sequencing method
Bioinformatic analyses of genomic and transcriptomic data