GENES FOR VASCULAR MORPHOGENESIS: A GENETIC APPROACH

Summary

Principal Investigator: Qing Kenneth Wang
Abstract: The long-term objective of our research is to discover the molecular mechanisms involved in the development of the cardiovascular system. We use the human genetic approach as the window into the genetic processes involved in the development of the heart and blood vessels. We are currently using this approach to identify the first gene for Klippel-Trenaunay syndrome (KTS), which is a vascular disease comprised of capillary, lymphatic, and venous malformations associated with bony and soft tissue hypertrophy. Because KTS is a vascular anomaly, we propose that KTS pathogenesis involves the disruption of the key genes for vascular morphogenesis during embryonic development. We have characterized a KTS translocation involving chromosomes 5 and 11, and identified a novel vascular gene, VEG5Q (Vascular Endothelial Gene on 5q), as the strong candidate gene for KTS. The goals of this proposal are to use these unique resources to functionally characterize the VEG5Q gene, to investigate its normal function involved in vascular morphogenesis, and to elucidate the pathogenic mechanisms of KTS-associated mutations. The specific aims are: 1) Molecular characterization of VEG5Q, a novel vascular gene and a strong candidate for KTS. 2) To generate mouse models that will elucidate the role of VEG5Q in vascular morphogenesis. 3) To identify proteins that interact with VEG5Q. 4) Genotype-phenotype correlation studies of KTS patients and identification/characterization of genes associated with 11p translocation breakpoint. 5) Identification of genes which are differentially expressed in KTS patients using the Gene-Chip technology. The successful accomplishment of goals in this study should allow us to understand the molecular mechanisms underlying KTS as well as other common vascular disorders such as varicose veins and venous malformations. The availability of KTS genes provides the groundwork and offers the exciting possibility of characterizing the molecular mechanisms underlying vascular morphogenesis. Moreover, understanding the genetic mechanisms underlying KTS offers possibilities for treatment of KTS as well as conditions such as cancer that depend on angiogenesis.
Funding Period: 2000-08-01 - 2005-07-31
more information: NIH RePORT

Top Publications

  1. ncbi Fluorescence in situ hybridization in cardiovascular disease
    Ayse Anil Timur
    Department of Molecular Cardiology, The Cleveland Clinic Foundation, OH, USA
    Methods Mol Med 128:11-21. 2006
  2. pmc Advances in the genetic basis of coronary artery disease
    Qing Wang
    Department of Molecular Cardiology, Lerner Research Institute ND4 38, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195, USA
    Curr Atheroscler Rep 7:235-41. 2005
  3. ncbi Proteomics with two-dimensional gel electrophoresis and mass spectrometry analysis in cardiovascular research
    Sun Ah You
    Department of Molecular Cardiology, The Cleveland Clinic Foundation, OH, USA
    Methods Mol Med 129:15-26. 2006
  4. ncbi Microarray analysis of cardiovascular diseases
    Stephen R Archacki
    Center for Molecular Genetics, The Cleveland Clinic Foundation, OH, USA
    Methods Mol Med 129:1-13. 2006
  5. ncbi High-throughput single-nucleotide polymorphisms genotyping: TaqMan assay and pyrosequencing assay
    Gong Qing Shen
    Center for Molecular Genetics, The Cleveland Clinic Foundation, OH, USA
    Methods Mol Med 128:209-24. 2006
  6. ncbi SAGE programs: model-free linkage analysis for complex cardiovascular phenotypes
    Shaoqi Rao
    Department of Molecular Cardiology, The Cleveland Clinic Foundation, OH, USA
    Methods Mol Med 128:61-89. 2006
  7. ncbi LINKAGE programs: linkage analysis for monogenic cardiovascular diseases
    Lin Li
    Department of Molecular Cardiology, The Cleveland Clinic Foundation, OH, USA
    Methods Mol Med 128:41-60. 2006
  8. ncbi Construction of somatic cell hybrid lines: fusion of mouse thymidine kinase-deficient 3T3 fibroblasts and human lymphoblastoid cells
    Ayse Anil Timur
    Department of Molecular Cardiology, The Cleveland Clinic Foundation, OH, USA
    Methods Mol Med 128:33-40. 2006
  9. pmc Mapping a new genetic locus for X linked retinitis pigmentosa to Xq28
    A Melamud
    J Med Genet 43:e27. 2006
  10. ncbi Loss of heterozygosity in human aberrant crypt foci (ACF), a putative precursor of colon cancer
    Liping Luo
    Institute of Pathology, Case Western Reserve University, Cleveland, OH 44106, USA
    Carcinogenesis 27:1153-9. 2006

Scientific Experts

  • Qing Kenneth Wang
  • Ayse Anil Timur
  • Sun Ah You
  • Gong Qing Shen
  • Shaoqi Rao
  • Xiao Li Tian
  • Liping Luo
  • Stephen R Archacki
  • A Melamud
  • Lin Li
  • A A Timur
  • L Li
  • D Chung
  • Theresa P Pretlow
  • E I Traboulsi
  • Karen A Stiffler
  • N S Peachey
  • S A Hagstrom
  • H Zegarra
  • Thomas G Pretlow
  • Q Xi
  • G Q Shen
  • E Simpson
  • Albert Luo
  • D J Driscoll

Detail Information

Publications15

  1. ncbi Fluorescence in situ hybridization in cardiovascular disease
    Ayse Anil Timur
    Department of Molecular Cardiology, The Cleveland Clinic Foundation, OH, USA
    Methods Mol Med 128:11-21. 2006
    ..FISH is also widely used in clinical diagnosis of chromosomal disorders...
  2. pmc Advances in the genetic basis of coronary artery disease
    Qing Wang
    Department of Molecular Cardiology, Lerner Research Institute ND4 38, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195, USA
    Curr Atheroscler Rep 7:235-41. 2005
    ..These studies identify a new mechanism, the myocyte enhancer factor 2 (MEF2) signaling pathway of vascular endothelium, for the pathogenesis of CAD, and also confirm the role of inflammation in the disease process...
  3. ncbi Proteomics with two-dimensional gel electrophoresis and mass spectrometry analysis in cardiovascular research
    Sun Ah You
    Department of Molecular Cardiology, The Cleveland Clinic Foundation, OH, USA
    Methods Mol Med 129:15-26. 2006
    ..This technique should be useful in characterizing cardiovascular diseases and in defining signaling pathways for cardiovascular development and physiology...
  4. ncbi Microarray analysis of cardiovascular diseases
    Stephen R Archacki
    Center for Molecular Genetics, The Cleveland Clinic Foundation, OH, USA
    Methods Mol Med 129:1-13. 2006
    ....
  5. ncbi High-throughput single-nucleotide polymorphisms genotyping: TaqMan assay and pyrosequencing assay
    Gong Qing Shen
    Center for Molecular Genetics, The Cleveland Clinic Foundation, OH, USA
    Methods Mol Med 128:209-24. 2006
    ..Here, we present the operative protocol, clarify the key technical issues, and highlight certain cautionary notes for high throughput SNP genotyping using TaqMan and pyrosequencing assays...
  6. ncbi SAGE programs: model-free linkage analysis for complex cardiovascular phenotypes
    Shaoqi Rao
    Department of Molecular Cardiology, The Cleveland Clinic Foundation, OH, USA
    Methods Mol Med 128:61-89. 2006
    ..In particular, the Haseman-Elston sib-pair regression method is introduced and implemented with examples to demonstrate how to identify susceptibility loci for complex traits...
  7. ncbi LINKAGE programs: linkage analysis for monogenic cardiovascular diseases
    Lin Li
    Department of Molecular Cardiology, The Cleveland Clinic Foundation, OH, USA
    Methods Mol Med 128:41-60. 2006
    ..Then, we demonstrate the usages of the programs by analyzing several examples of hypothetical pedigrees with the inheritance modes of autosomal-dominant, autosomal-recessive, and genetic heterogeneity...
  8. ncbi Construction of somatic cell hybrid lines: fusion of mouse thymidine kinase-deficient 3T3 fibroblasts and human lymphoblastoid cells
    Ayse Anil Timur
    Department of Molecular Cardiology, The Cleveland Clinic Foundation, OH, USA
    Methods Mol Med 128:33-40. 2006
    ..These hybrid cells serve as an excellent tool with which to define the exact chromosomal breakpoints involved in a cytogenetic abnormality and to identify genes at the breakpoints...
  9. pmc Mapping a new genetic locus for X linked retinitis pigmentosa to Xq28
    A Melamud
    J Med Genet 43:e27. 2006
    ..06, 2.17, and 2.20, respectively. Haplotype analysis revealed segregation of the disease phenotype with markers at Xq28...
  10. ncbi Loss of heterozygosity in human aberrant crypt foci (ACF), a putative precursor of colon cancer
    Liping Luo
    Institute of Pathology, Case Western Reserve University, Cleveland, OH 44106, USA
    Carcinogenesis 27:1153-9. 2006
    ..The finding of 3 of 4 of the losses of heterozygosity at 11p11 for PTPRJ and half of all the losses of heterozygosity in this study at PTPRJ suggest that this gene plays a role early in colon neoplasia...
  11. pmc Update on the molecular genetics of vascular anomalies
    Qing K Wang
    Department of Molecular Cardiology and Center for Cardiovascular Genetics, Lerner Research Institute ND 40, The Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195, USA
    Lymphat Res Biol 3:226-33. 2005
    ..Furthermore, these studies have identified critical genes involved in vascular morphogenesis, and provided fundamental understanding of the molecular mechanisms underlying vasculogenesis and angiogenesis...
  12. ncbi Ferritin in atherosclerosis
    Sun Ah You
    Center for Molecular Genetics, Department of Molecular Cardiology, ND4 38, Lerner Research Institute, and Center for Cardiovascular Genetics, The Cleveland Clinic Foundation, 9500 Euclid Ave, Cleveland, OH 44195, USA
    Clin Chim Acta 357:1-16. 2005
    ..Future studies will determine whether increased ferritin levels can serve as a distinct biomarker for the incidence of CAD/MI and distinguish whether increased ferritin levels are a cause of CAD or a consequence of the disease process...
  13. pmc Biomedicine and diseases: the Klippel-Trenaunay syndrome, vascular anomalies and vascular morphogenesis
    A A Timur
    Center for Molecular Genetics, ND40, Lerner Research Institute, The Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, Ohio 44195, USA
    Cell Mol Life Sci 62:1434-47. 2005
    ....
  14. pmc Molecular genetics of coronary artery disease
    Qing Wang
    Department of Molecular Cardiology, Lerner Research Institute, The Cleveland Clinic Foundation, Cleveland, OH 44195, USA
    Curr Opin Cardiol 20:182-8. 2005
    ..Many advances have recently been made, however, and these are reviewed here...
  15. ncbi Generation of transgenic mice for cardiovascular research
    Xiao Li Tian
    Department of Molecular Cardiology, The Cleveland Clinic Foundation, OH, USA
    Methods Mol Med 129:69-81. 2006
    ....