Chemical and Genetic Modifiers of the Protein C Pathway

Summary

Principal Investigator: David A Buchner
Abstract: Venous thrombosis affects approximately 1/1,000 individuals per year. Most cases involve 1 or more complex genetic factors together with a range of environmental triggers. The majority of monogenic cases of familial thrombosis are associated with defects in the protein C (PC) pathway. It would be of tremendous clinical significance to find genes that modulate the penetrance of mutations in the PC pathway. PC knockout zebrafish will be generated from frozen sperm corresponding to 2 previously identified null alleles of PC, identified in a library of DNA from ENU mutagenized zebrafish. These fish will be used in a sensitized genome-wide ENU mutagenesis screen to identify suppressors of the lethal thrombosis. Heritable mutations will be identified by positional cloning. In addition, the PC knockout zebrafish will be used in a second high-throughput screen to identify novel anticoagulants. The strengths of the zebrafish model organism will again be exploited to assay a diverse set of 35,000 small molecule compounds for in vivo rescue of the lethal phenotype. Successfully rescuing compounds can be quickly tested in human plasma coagulation assays and in vivo mouse models to determine their target and evaluate their therapeutic potential.
Funding Period: 2005-09-30 - 2008-09-29
more information: NIH RePORT

Top Publications

  1. pmc Ancestral paternal genotype controls body weight and food intake for multiple generations
    Soha N Yazbek
    Department of Genetics, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA
    Hum Mol Genet 19:4134-44. 2010
  2. pmc Deep congenic analysis identifies many strong, context-dependent QTLs, one of which, Slc35b4, regulates obesity and glucose homeostasis
    Soha N Yazbek
    Department of Genetics, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA
    Genome Res 21:1065-73. 2011
  3. pmc pak2a mutations cause cerebral hemorrhage in redhead zebrafish
    David A Buchner
    Howard Hughes Medical Institute and Life Sciences Institute, University of Michigan, Ann Arbor, MI 48109, USA
    Proc Natl Acad Sci U S A 104:13996-4001. 2007
  4. pmc Resistance to diet-induced obesity in mice with a single substituted chromosome
    David A Buchner
    Department of Genetics, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106 4955, USA
    Physiol Genomics 35:116-22. 2008

Scientific Experts

  • Joseph H Nadeau
  • David A Buchner
  • Soha N Yazbek
  • Sabrina H Spiezio
  • Colleen M Croniger
  • Lindsay C Burrage
  • Gabriel E Zentner
  • Chang Wen Hsieh
  • Jonathan M Geisinger
  • Peter C Scacheri
  • William E O'Brien
  • Annie E Hill
  • Fengyun Su
  • Pudur Jagadeeswaran
  • Julio D Amigo
  • Linda K Barthel
  • David Ginsburg
  • Beth McGee
  • Brant M Weinstein
  • Susan E Lyons
  • Andrew W Hanosh
  • Makoto Kamei
  • Jennifer S Yamaoka
  • Seongcheol Kim
  • Daniel Goldman
  • Nathan D Lawson
  • Jordan A Shavit
  • Pamela A Raymond

Detail Information

Publications4

  1. pmc Ancestral paternal genotype controls body weight and food intake for multiple generations
    Soha N Yazbek
    Department of Genetics, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA
    Hum Mol Genet 19:4134-44. 2010
    ..Persistence of these phenotypes across multiple generations raises the possibility that transgenerational genetic effects contribute to current metabolic conditions...
  2. pmc Deep congenic analysis identifies many strong, context-dependent QTLs, one of which, Slc35b4, regulates obesity and glucose homeostasis
    Soha N Yazbek
    Department of Genetics, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA
    Genome Res 21:1065-73. 2011
    ..This work demonstrated the unique power of CSSs as a platform for studying complex genetic traits and identifying QTLs...
  3. pmc pak2a mutations cause cerebral hemorrhage in redhead zebrafish
    David A Buchner
    Howard Hughes Medical Institute and Life Sciences Institute, University of Michigan, Ann Arbor, MI 48109, USA
    Proc Natl Acad Sci U S A 104:13996-4001. 2007
    ..These data provide in vivo evidence for a critical function of Pak2 in vascular integrity and demonstrate a severe disease phenotype resulting from loss of Pak2 function...
  4. pmc Resistance to diet-induced obesity in mice with a single substituted chromosome
    David A Buchner
    Department of Genetics, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106 4955, USA
    Physiol Genomics 35:116-22. 2008
    ..A better understanding of these genotype-phenotype relationships may enable a more individualized diagnosis and treatment of obesity and the metabolic syndrome...