Leah Solberg Woods, PhD
Associate Professor, Pediatrics
Specialization: Genetics of Type 2 Diabetes
Solberg Woods Lab
Genetics of Type 2 Diabetes and Obesity
My laboratory is interested in identifying genes involved in type 2 diabetes (T2D) using rat models. T2D is a growing health problem with 347 million people affected worldwide. Prevalence in the United States is expected to more than double by 2050, with alarming increases in children and adolescents. T2D is a disease of relative insulin deficiency; or an inability to secrete sufficient insulin to compensate for insulin resistance. This disease is the leading cause of kidney failure, blindness and limb amputation and a major risk factor for heart disease and stroke. T2D is a complex disorder affected by multiple environmental and genetic components. While genome-wide association studies in humans have recently identified over 60 genes for T2D, these genes explain only a small portion of the heritable variance, indicating many genes have not yet been identified.
We are using a genetic rat model, outbred heterogeneous stock (HS) rats, to identify relatively small chromosomal regions that play a role in diabetes related phenotypes. HS rats are outbred from eight inbred rat strains such that the chromosomal make-up of the progeny is a mosaic of the founding inbred strains. This enables the mapping of chromosomal loci to only 2-4 Megabases, significantly decreasing the number of possible candidate genes within each region.
HS rats are ideal for studying T2D because alleles for both insulin resistance and beta cell dysfunction segregate within the colony. Our laboratory has fine-mapped a 3.8 Mb region on rat chromosome 1 that is involved in glucose tolerance and insulin resistance. Using founder sequence and expression analysis, we identified two-pore channel segment 2 (Tpcn2), as the likely causative gene underlying this locus. We are now using HS rats to identify additional loci that play a role in metabolic phenotypes across the entire rat genome. Once genes are identified, we will test these genes in human cohorts as well as use rat models to understand the mechanism of disease. In addition, we are forming collaborations with other investigators to use HS rats to study other complex traits including kidney disease and behaviors involved in drug addiction. Our data indicate that HS rats are a useful model for uncovering the underlying genetic basis of several complex traits, including diabetes, obesity, kidney disease and drug-abuse behaviors.