Keum and Bennett Receive ASM Best Poster Award

June 29, 2011

Durham, N.C. — Sehoon Keum, a postdoctoral associate, and Chris Bennett, a graduate student in the University Program in Genetics and Genomics (UPGG), have received Best Poster Awards for their presentations entitled, Genetic modifiers in response to ischemia and A locus mapping to mouse chromosome 8 determines infarct volume in a mouse model of ischemic stroke, respectively. These awards were given for the best poster presentations at the Mouse Genetics 2011 Conference in Washington, DC, June 22-25.

Keum and Bennett both work in the laboratory of Doug Marchuk, PhD, Professor and Vice Chair of the Department of Molecular Genetics and Microbiology and Director of the Duke University Program in Genetics and Genomics. Keum joined the Marchuk lab in 2005 to study genetic risk factors critical to infarction damage from focal cerebral ischemia (stroke) using mouse QTL analysis. Bennett joined the lab in 2011, and his current research is aimed at understanding the lesser known aspects of human cardiovascular disease visualized through mouse models.

Sehoon Keum_ASM Poster Awd_June 2011 News ItemGenetic modifiers in response to ischemia (Sehoon Keum)
In a mouse model of ischemic stroke, infarct volume is highly variable and strain dependent, but the natural genetic determinants responsible for this difference remain unknown. After permanent distal middle cerebral artery occlusion (MCAO), infarct volume was determined for 16 inbred mouse strains, chromosome substitution strains, and for two intercross cohorts, F2(B6xBALB/c) and F2(B6xSWR/J). Infarct volume varied up to 30-fold between strains, with heritability estimated at 0.88. To identify genetic determinants modulating infarct tissue damage, we performed quantitative trait locus (QTL) analysis of surgically induced cerebral infarct volume. We have identified multiple quantitative trait loci (QTL) that modulate infarct volume, with a major locus (Civq1) on chromosome 7 accounting for over 50% of the variation, with a combined LOD score of 21.7. Measurement of infarct volume in chromosome substitution strains (CSS) and two additional intercrosses validate that Civq1 on chromosome 7 is present in multiple inbred strains. Interval-specific ancestral SNP haplotype analysis for Civq1 results in 5 candidate genes. A causative gene underlying Civq1 may regulate collateral artery formation and genetic variations in the gene may result in the differential outcome of cerebral infarction. Interestingly, Civq1 appears to be identical to Lsq1, a locus conferring limb salvage and reperfusion in hindlimb ischemia. The identification of the genes underlying these loci may uncover novel genetic and physiological pathways that modulate cerebral infarction and provide new targets for therapeutic intervention in ischemic stroke, and possibly other human vascular occlusive diseases.

Chris Bennett_ASM Poster Awd_June 2011 News ItemA locus mapping to mouse chromosome 8 determines infarct volume in a mouse model of ischemic stroke (Chris Bennett)
In an established mouse model of focal cerebral ischemia, infarct volume is highly variable and strain dependent, but the natural genetic determinants remain unknown.  To identify these genetic determinants regulating ischemic neuronal damage and to dissect apart the role of individual genes and physiological mechanisms in infarction in mice, we performed quantitative trait locus analysis of surgically induced cerebral infarct volume.  After permanent occlusion of the distal middle cerebral artery, infarct volume was determined for 30 inbred strains of mice.  Genome-wide linkage analysis was performed for infarct volume as a quantitative trait.  Infarct volume varied up to 50-fold between strains, with heritability estimated at 0.88.  Overall, 3 quantitative trait loci were identified that modulate infarct volume between B6 and BALB/C.  One of these loci mapped to chromosome 8 in a 32mb region with a suggestive LOD score of 3.2.  Subsequent genome wide association studies (GWAS) have narrowed down this region and identified a second adjacent region.  Current studies on candidates with significant biological relevance are aimed at identifying strain-dependent expression profiles and targeted exonic sequencing. The identification of the gene in this loci may uncover novel genetic and physiological pathways implicated in the modulation of cerebral infarction and provide new targets for therapeutic intervention in ischemic stroke, and even further in other ischemic diseases.
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