Genetic and Developmental Basis of Pediatric Aortic Valve Disease Pathogenesis

Summary

Principal Investigator: Robert B Hinton
Affiliation: Cincinnati Children's Hospital Medical Center
Country: USA
Abstract: The Candidate is a pediatric cardiologist who is completing a post-doctoral research fellowship in cardiovascular genetics and developmental biology to gain the skills necessary to pursue an academic career in patient-oriented research. His long-term goal is to become an independent physician scientist, and to contribute to the understanding of the molecular mechanisms underlying pediatric heart disease. By applying the complementary approaches of human genetics and cardiac development, he will cultivate a 'bedside to bench to bedside" approach to investigate the genetic causes and pathogenesis of pediatric aortic valve disease. Such an approach promises to provide a foundation for developing improved and novel diagnostic modalities, therapeutic interventions and preventive strategies for this important clinical problem. The objective of this proposal is to identify new genetic loci linked to aortic valve malformation and to elucidate the pathogenesis of pediatric aortic valve disease. The central hypothesis is that aortic valve disease pathogenesis is mediated by gene mutations that regulate extracellular matrix (ECM) organization during valve development thereby resulting in valve disease. Using families identified by a hypoplastic left heart syndrome (HLHS) proband, parametric and nonparametric linkage analysis will be performed to identify aortic valve disease-causing genes. The hypothesis is that HLHS is a severe form of aortic valve disease and is inherited as an autosomal recessive form of bicuspid aortic valve (BAV). Using explanted pediatric BAVs, the relationship between BAV morphology, ECM organization and valve disease type will be determined. To better define dysregulation of ECM remodeling as a cause of pediatric aortic valve disease, mechanistic analyses of ECM organization will be performed using a mouse model of elastin haploinsufficiency. The hypothesis is that elastin haploinsufficiency mediates dysregulation of ECM protein synthesis resulting in valve ECM disorganization and valve dysfunction. The rationale for the proposed studies is based upon preliminary data. Successful completion of the proposed studies will advance our understanding of pediatric valve disease. The Candidate is dedicated to a research career in pediatric cardiovascular medicine. His environment is exceptionally supportive as evidenced by an invested and accomplished Mentor and a generous and collaborative research environment renowned for its molecular and clinical cardiology programs. These factors create an ideal environment for professional development. A Career Development Award will allow the Candidate to devote 80% effort to patient-oriented research, and to obtain the training necessary to transition to an independent investigator. (End of Abstract)
Funding Period: 2006-08-03 - 2011-04-30
more information: NIH RePORT

Top Publications

  1. ncbi Evidence in favor of linkage to human chromosomal regions 18q, 5q and 13q for bicuspid aortic valve and associated cardiovascular malformations
    Lisa J Martin
    Center for Epidemiology and Biostatistics, University of Cincinnati, Cincinnati Children s Hospital Medical Center, Cincinnati, OH 45229, USA
    Hum Genet 121:275-84. 2007
  2. pmc Hypoplastic left heart syndrome links to chromosomes 10q and 6q and is genetically related to bicuspid aortic valve
    Robert B Hinton
    Division of Cardiology, Cincinnati Children s Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH 45229 3039, USA
    J Am Coll Cardiol 53:1065-71. 2009
  3. pmc The presence of bicuspid aortic valve does not predict ventricular septal defect type
    Kan N Hor
    Division of Cardiology, Cincinnati Children s Hospital Medical Center, Cincinnati, Ohio 45229, USA
    Am J Med Genet A 146:3202-5. 2008
  4. pmc Prenatal head growth and white matter injury in hypoplastic left heart syndrome
    Robert B Hinton
    Division of Cardiology, Cincinnati Children s Hospital Medical Center, Cincinnati, Ohio 45229, USA
    Pediatr Res 64:364-9. 2008
  5. pmc The family history: reemergence of an established tool
    Robert B Hinton
    Division of Cardiology, MLC 2003, Cincinnati Children s Hospital Medical Center, Cincinnati, OH 45229 3039, USA
    Crit Care Nurs Clin North Am 20:149-58, v. 2008
  6. doi Mouse heart valve structure and function: echocardiographic and morphometric analyses from the fetus through the aged adult
    Robert B Hinton
    Division of Cardiology, Cincinnati Children s Hospital Medical Center, Cincinnati, Ohio 45229 3039, USA
    Am J Physiol Heart Circ Physiol 294:H2480-8. 2008
  7. ncbi Novel fibrillin 1 mutation in a case of neonatal Marfan syndrome: the increasing importance of early recognition
    Jamie Sutherell
    Division of Cardiology, Cincinnati Children s Hospital Medical Center, Cincinnati, OH 45229 3039, USA
    Congenit Heart Dis 2:342-6. 2007
  8. ncbi Hypoplastic left heart syndrome is heritable
    Robert B Hinton
    Division of Cardiology, Cincinnati Children s Hospital Medical Center, Cincinnati, Ohio 45229 3039, USA
    J Am Coll Cardiol 50:1590-5. 2007
  9. ncbi BMP and FGF regulatory pathways in semilunar valve precursor cells
    Bin Zhao
    Division of Cardiology, MLC 7042, Cincinnati Children s Hospital Medical Center, Cincinnati, Ohio 45229, USA
    Dev Dyn 236:971-80. 2007
  10. doi Replacement of the aortic valve in a patient with mucolipidosis III
    Linda H Cripe
    The Heart Institute, Cincinnati Children s Hospital Medical Center and the University of Cincinnati College of Medicine, Cincinnati, Ohio
    Cardiol Young 19:641-3. 2009

Scientific Experts

  • Robert B Hinton
  • Linda H Cripe
  • D Woodrow Benson
  • Kan N Hor
  • Lisa J Martin
  • Bin Zhao
  • Jamie Sutherell
  • Stephanie M Ware
  • William L Border
  • Bradley T Tinkle
  • Kerry Shooner
  • Meredith Tabangin
  • Yuri Zarate
  • Robert J Hopkin
  • Gregor Andelfinger
  • Laura Etter
  • Mehdi Keddache
  • James C Hyland
  • David Witte
  • Larry W Markham
  • Vijaya Ramachandran

Detail Information

Publications10

  1. ncbi Evidence in favor of linkage to human chromosomal regions 18q, 5q and 13q for bicuspid aortic valve and associated cardiovascular malformations
    Lisa J Martin
    Center for Epidemiology and Biostatistics, University of Cincinnati, Cincinnati Children s Hospital Medical Center, Cincinnati, OH 45229, USA
    Hum Genet 121:275-84. 2007
    ..These regions likely contain genes whose mutation results in BAV and/or associated CVM indicating their important role in valvulogenesis and cardiac development...
  2. pmc Hypoplastic left heart syndrome links to chromosomes 10q and 6q and is genetically related to bicuspid aortic valve
    Robert B Hinton
    Division of Cardiology, Cincinnati Children s Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH 45229 3039, USA
    J Am Coll Cardiol 53:1065-71. 2009
    ..This study was designed to identify disease loci for hypoplastic left heart syndrome (HLHS) and evaluate the genetic relationship between HLHS and bicuspid aortic valve (BAV)...
  3. pmc The presence of bicuspid aortic valve does not predict ventricular septal defect type
    Kan N Hor
    Division of Cardiology, Cincinnati Children s Hospital Medical Center, Cincinnati, Ohio 45229, USA
    Am J Med Genet A 146:3202-5. 2008
    ..This may be due to phenotypic and genetic heterogeneity of BAV and VSD, other modifying factors as manifested by differences in associated CVM, as well as limitations of the clinical taxonomy of VSD...
  4. pmc Prenatal head growth and white matter injury in hypoplastic left heart syndrome
    Robert B Hinton
    Division of Cardiology, Cincinnati Children s Hospital Medical Center, Cincinnati, Ohio 45229, USA
    Pediatr Res 64:364-9. 2008
    ..Brains from HLHS fetuses demonstrated chronic diffuse white matter injury of varying severity. These patterns of prenatal head growth and brain histopathology identify a spectrum of abnormal CNS development and/or injury in HLHS fetuses...
  5. pmc The family history: reemergence of an established tool
    Robert B Hinton
    Division of Cardiology, MLC 2003, Cincinnati Children s Hospital Medical Center, Cincinnati, OH 45229 3039, USA
    Crit Care Nurs Clin North Am 20:149-58, v. 2008
    ..The increasing use of genetic screening promises to cultivate a paradigm shift in medical treatment emphasizing primary prevention and early intervention. Appreciation of the family history is necessary to make this important advance...
  6. doi Mouse heart valve structure and function: echocardiographic and morphometric analyses from the fetus through the aged adult
    Robert B Hinton
    Division of Cardiology, Cincinnati Children s Hospital Medical Center, Cincinnati, Ohio 45229 3039, USA
    Am J Physiol Heart Circ Physiol 294:H2480-8. 2008
    ....
  7. ncbi Novel fibrillin 1 mutation in a case of neonatal Marfan syndrome: the increasing importance of early recognition
    Jamie Sutherell
    Division of Cardiology, Cincinnati Children s Hospital Medical Center, Cincinnati, OH 45229 3039, USA
    Congenit Heart Dis 2:342-6. 2007
    ..Because of potential new therapies, it is increasingly important to recognize neonatal MFS in utero as well as shortly after birth to initiate the appropriate diagnostic work-up and management...
  8. ncbi Hypoplastic left heart syndrome is heritable
    Robert B Hinton
    Division of Cardiology, Cincinnati Children s Hospital Medical Center, Cincinnati, Ohio 45229 3039, USA
    J Am Coll Cardiol 50:1590-5. 2007
    ..This study sought to determine the size of the genetic effect (heritability) in families identified by a hypoplastic left heart syndrome (HLHS) proband...
  9. ncbi BMP and FGF regulatory pathways in semilunar valve precursor cells
    Bin Zhao
    Division of Cardiology, MLC 7042, Cincinnati Children s Hospital Medical Center, Cincinnati, Ohio 45229, USA
    Dev Dyn 236:971-80. 2007
    ....
  10. doi Replacement of the aortic valve in a patient with mucolipidosis III
    Linda H Cripe
    The Heart Institute, Cincinnati Children s Hospital Medical Center and the University of Cincinnati College of Medicine, Cincinnati, Ohio
    Cardiol Young 19:641-3. 2009
    ..As life expectancy increases for patients with lysosomal storage disorders, approaches to intervention for valvar disease become increasingly important...