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 Somatic growth trajectory in the fetus with hypoplastic left heart syndrome
    James F Cnota
    Division of Cardiology, Cincinnati Children s Hospital Medical Center, Cincinnati, OH, USA
    Pediatr Res 74:284-9. 2013
  2. ncbi Microcephaly is associated with early adverse neurologic outcomes in hypoplastic left heart syndrome
    Patrick T Hangge
    Division of Cardiology, The Heart Institute, Cincinnati Children s Hospital Medical Center, Cincinnati, OH, USA
    Pediatr Res 74:61-7. 2013
  3. pmc Twist1 promotes heart valve cell proliferation and extracellular matrix gene expression during development in vivo and is expressed in human diseased aortic valves
    Santanu Chakraborty
    The Heart Institute, Cincinnati Children s Medical Center, Cincinnati, OH 45229, USA
    Dev Biol 347:167-79. 2010
  4. doi Heart valve structure and function in development and disease
    Robert B Hinton
    Division of Cardiology, The Heart Institute, Cincinnati Children s Hospital Medical Center, Ohio 45229, USA
    Annu Rev Physiol 73:29-46. 2011
  5. pmc Regional structure-function relationships in mouse aortic valve tissue
    Varun K Krishnamurthy
    Department of Biomedical Engineering, University of Cincinnati, Cincinnati, OH, USA
    J Biomech 44:77-83. 2011
  6. pmc Differential expression of cartilage and bone-related proteins in pediatric and adult diseased aortic valves
    Elaine E Wirrig
    Division of Molecular Cardiovascular Biology, The Heart Institute, Cincinnati Children s Hospital Medical Center, Cincinnati, OH 45229, USA
    J Mol Cell Cardiol 50:561-9. 2011
  7. doi Risk factors for aortic valve disease in bicuspid aortic valve: a family-based study
    Troy J Calloway
    Division of Cardiology, Cincinnati Children s Hospital Medical Center, Ohio 45229 3039, USA
    Am J Med Genet A 155:1015-20. 2011
  8. pmc Inhibitory role of Notch1 in calcific aortic valve disease
    Asha Acharya
    Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America
    PLoS ONE 6:e27743. 2011
  9. pmc Maladaptive matrix remodeling and regional biomechanical dysfunction in a mouse model of aortic valve disease
    Varun K Krishnamurthy
    Division of Cardiology, The Heart Institute, Cincinnati Children s Hospital Medical Center, Cincinnati, OH 45229, USA
    Matrix Biol 31:197-205. 2012
  10. pmc Elastin haploinsufficiency results in progressive aortic valve malformation and latent valve disease in a mouse model
    Robert B Hinton
    Division of Cardiology, Cincinnati Children s Hospital Medical Center, Cincinnati, Ohio 45229 3039, USA
    Circ Res 107:549-57. 2010

Scientific Experts

  • Robert B Hinton
  • Vidu Garg
  • Linda H Cripe
  • Varun K Krishnamurthy
  • D Woodrow Benson
  • Patrick T Hangge
  • James F Cnota
  • Elaine E Wirrig
  • Lisa J Martin
  • Jessica G Woo
  • Andrea C Hinton
  • Allison A Divanovic
  • Daria A Narmoneva
  • Farshid Guilak
  • Troy J Calloway
  • Asha Acharya
  • Katherine E Yutzey
  • Walter H Merrill
  • Santanu Chakraborty
  • Kan N Hor
  • Bin Zhao
  • Jamie Sutherell
  • Richard F Ittenbach
  • Yu Wang
  • Erik C Michelfelder
  • Peter B Manning
  • Amy M Opoka
  • Christine B Kern
  • Haley A Nichols
  • Harold R Garner
  • Animesh Tandon
  • Cristi L Galindo
  • Sara N Koenig
  • Chetan P Hans
  • Xue Zhang
  • Douglas B Spicer
  • 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

Publications21

  1. ncbi Somatic growth trajectory in the fetus with hypoplastic left heart syndrome
    James F Cnota
    Division of Cardiology, Cincinnati Children s Hospital Medical Center, Cincinnati, OH, USA
    Pediatr Res 74:284-9. 2013
    ..Fetal growth trajectory has not been described. We hypothesized that fetal growth trajectory declines across late gestation in this population...
  2. ncbi Microcephaly is associated with early adverse neurologic outcomes in hypoplastic left heart syndrome
    Patrick T Hangge
    Division of Cardiology, The Heart Institute, Cincinnati Children s Hospital Medical Center, Cincinnati, OH, USA
    Pediatr Res 74:61-7. 2013
    ..We hypothesized that poor fetal head growth is associated with an increased frequency of adverse clinical outcomes...
  3. pmc Twist1 promotes heart valve cell proliferation and extracellular matrix gene expression during development in vivo and is expressed in human diseased aortic valves
    Santanu Chakraborty
    The Heart Institute, Cincinnati Children s Medical Center, Cincinnati, OH 45229, USA
    Dev Biol 347:167-79. 2010
    ..Overall, these data implicate Twist1 as a critical regulator of valve development and suggest that Twist1 influences ECM production and cell proliferation during disease...
  4. doi Heart valve structure and function in development and disease
    Robert B Hinton
    Division of Cardiology, The Heart Institute, Cincinnati Children s Hospital Medical Center, Ohio 45229, USA
    Annu Rev Physiol 73:29-46. 2011
    ..Further studies are necessary to determine regulatory pathway interactions underlying valve pathogenesis in order to generate new avenues for novel therapeutics...
  5. pmc Regional structure-function relationships in mouse aortic valve tissue
    Varun K Krishnamurthy
    Department of Biomedical Engineering, University of Cincinnati, Cincinnati, OH, USA
    J Biomech 44:77-83. 2011
    ..The micropipette aspiration technique provides a promising approach for studies of valve structure and function in small animal models, such as transgenic mouse models of valve disease...
  6. pmc Differential expression of cartilage and bone-related proteins in pediatric and adult diseased aortic valves
    Elaine E Wirrig
    Division of Molecular Cardiovascular Biology, The Heart Institute, Cincinnati Children s Hospital Medical Center, Cincinnati, OH 45229, USA
    J Mol Cell Cardiol 50:561-9. 2011
    ..These findings provide specific molecular indicators of AoVD progression, which may lead to identification of early disease markers and the development of potential therapeutics...
  7. doi Risk factors for aortic valve disease in bicuspid aortic valve: a family-based study
    Troy J Calloway
    Division of Cardiology, Cincinnati Children s Hospital Medical Center, Ohio 45229 3039, USA
    Am J Med Genet A 155:1015-20. 2011
    ..BAV is determined largely by genetic effects, but the phenotypic variability of AVD is primarily determined by nongenetic factors. BAV morphology may have predictive value for the time course of AVD...
  8. pmc Inhibitory role of Notch1 in calcific aortic valve disease
    Asha Acharya
    Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America
    PLoS ONE 6:e27743. 2011
    ..Finally, the addition of Sox9 was able to prevent the calcification of porcine AVICs that occurs with Notch inhibition. In conclusion, loss of Notch signaling contributes to aortic valve calcification via a Sox9-dependent mechanism...
  9. pmc Maladaptive matrix remodeling and regional biomechanical dysfunction in a mouse model of aortic valve disease
    Varun K Krishnamurthy
    Division of Cardiology, The Heart Institute, Cincinnati Children s Hospital Medical Center, Cincinnati, OH 45229, USA
    Matrix Biol 31:197-205. 2012
    ..Combining molecular and engineering approaches provides complementary mechanistic insights that may be informative in the search for new therapeutic targets and durable valve bioprostheses...
  10. pmc Elastin haploinsufficiency results in progressive aortic valve malformation and latent valve disease in a mouse model
    Robert B Hinton
    Division of Cardiology, Cincinnati Children s Hospital Medical Center, Cincinnati, Ohio 45229 3039, USA
    Circ Res 107:549-57. 2010
    ..Because elastic fiber abnormalities are a central feature of degenerative valve disease, we hypothesized that elastin-insufficient mice would manifest viable heart valve disease...
  11. pmc A fetus with hypertrophic cardiomyopathy, restrictive, and single-ventricle physiology, and a beta-myosin heavy chain mutation
    Robert B Hinton
    Division of Cardiology, Cincinnati Children s Hospital Medical Center, Cincinnati, OH 45229, USA
    J Pediatr 157:164-6. 2010
    ..We describe a patient with a pathogenic familial beta-myosin heavy chain mutation who was prenatally diagnosed with left ventricular hypoplasia and restrictive diastolic physiology...
  12. ncbi 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...
  13. 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
    ....
  14. 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...
  15. 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...
  16. 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
    ....
  17. 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...
  18. 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...
  19. 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...
  20. 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)...
  21. 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...