GENETICS & GENOMICS

Research in the field of genetics and genomics focuses on the analysis of complex and common disorders and their underlying genetic basis using animal and human studies. Investigators use animal models consomic and congenic rat strains, knock-out and transgenic rats and mice) or human studies combined with linkage analysis, single nucleotide polymorphism (SNP)-based association studies, and functional genomic analyses using transgenic rat and mouse models, microarray expression profiling, and siRNA to understand the mechanisms by which mutations affect organ function and integrity and ultimately lead to common disorders.

Genetic Analysis of Hypertension and other Cardiovascular Disorders
Genetic linkage studies and the development of genetically modified rats are major areas of research in the department. Chromosomal substitution studies ranging from the whole chromosome (consomic rats) to very small chromosomal inserts (congenic rats) are ongoing in an effort to identify regions of the genome and genes within these regions that interact to control complex functional pathways related to hypertension and other cardiovascular abnormalities. Large custom-gene microarrays are being used to define candidate genes within these chromosomal regions of interest.

These studies are complemented by ongoing efforts to identify and characterize the genetic basis for hypertension and myocardial ischemia in human patient cohorts. A family-based cohort group from the Saguenay-Lac St. Jean region in Quebec/Canada, and a cohort of individuals from the African American community in Milwaukee , Wisconsin , are being used to decipher the genetic basis of hypertension, and 2,000 participants have been included in an ongoing study to identify the genetic basis of myocardial infarction and left ventricular hypertrophy.

Genetic Analysis of End-Stage Renal Disease
End-stage renal disease (ESRD) usually occurs as chronic renal failure progresses to the point where kidney function is less than 10% of baseline. At this point, the patient will require dialysis or kidney transplantation, otherwise complications are multiple and severe and death will occur from accumulation of fluids and waste products in the body. ESRD almost always follows chronic kidney failure, which may exist for 10 to 20 years or more before progression to ESRD. Efforts in the department to elucidate the genetic basis of ESRD have utilized rat models as well as human studies. Linkage analyses in crosses of rat strains susceptible to ESRD have identified a number of quantitative trait loci (QTL) that are currently being investigated using consomic and congenic animal models. Human studies have recruited more than 30,000 participants for analysis.

Genetic Analysis of Diabetes
Our studies focus on analysis of the genetic factors that lead to the development of diabetes in rat models. These efforts have led to the positional cloning of a gene contributing to Type 1 Diabetes in the Biobreeding (BB) rat, and to identification of the causal mutation in a member of a novel gene family, Gimap5, that causes T-cell lymphopenia and early progression to diabetes. Members of the department are currently investigating coding and non-coding regions of the gene region by generating transgenic rat models to validate candidate genes and sequence variants identified by a spectrum of genetic and genomics tests (consomic, expression arrays) as being causal factors underlying diabetes. In a transgenic rescue approach utilizing a long stretch of DNA (BAC), the positionally cloned gene Gimap5 (Ian5) has been validated and is now being investigated as to its involvement in the pathogenesis of lymphopenia and Type 1 diabetes.

Other ongoing studies into the genetic basis of diabetes use consomic and congenic rat strains to map loci that confer delayed onset of diabetes, and analyze molecular pathways mediating the development of various diabetic complications. We have projects that are focused on the role of thiol-related genes in diabetes as well as a number of tissue culture models of high ambient glucose.

Genetic Analysis of Obesity
Obesity is a major health problem in the U.S., and its incidence is rapidly increasing. It is believed that genetic susceptibility as well as lifestyle significantly contribute to the development and progression of the disease, and ultimately lead to associated co-morbidities such as diabetes and cardiovascular complications. Unfortunately, to date only a few genes have been identified as contributing to the disease development in humans.

Research efforts in the department focus on identification and analysis of genetic susceptibility genes through linkage, and association analysis in human family-based cohorts. More than 3,000 people have been included in these studies and several genes have been shown to be associated with the disorder. In addition, linkage analyses have identified a large number of quantitative trait loci (QTL) linked to phenotypes representative of obesity. Our current efforts focus on fine-mapping the causal mutations in these families and further examining the genes in other unrelated patient cohorts.

Genetic Analysis of Respiratory Disorders
Studies in the department use different animal models to gain insight into the time-course of normal development of the ventilatory control system, as well as the effect of environmental and genetic influences on these changes during development. A newborn piglet model is being used to determine whether a critical window of development exists in the ventilatory control system that has been proposed as a part of a triple-risk model in Sudden Infant Death Syndrome. In addition, the interaction of plasticity and genetic influences is being studied using inbred strains of rats exposed to perinatal hyperoxia.

Other projects use consomic rat models generated as part of the Program for Genomic Applications (PGA) to elucidate genes that contribute to the control of breathing. In combination, these studies are aimed at understanding how the ventilatory control system matures under both normal and stressed conditions. All these studies relate primarily to disease conditions of central and obstructive sleep apnea, Sudden Infant Death syndrome, congenital central alveolar hypoventilation, and traumatic brainstem injury.