Prevention of HPE in a mouse model susceptible to retinoic acid teratogenicity

Summary

Principal Investigator: Anna Petryk
Abstract: DESCRIPTION (provided by applicant): There is a fundamental gap in understanding the mechanisms of gene-environment interactions in the pathogenesis of craniofacial defects. The existence of this gap hinders our ability to prevent defects in at risk individuals. Our long-term goal is to understand the underlying mechanisms that predispose patients to craniofacial defects in order to design targeted preventive interventions. A mouse model deficient in Twisted gastrulation (TWSG1) allows us to study the underlying mechanisms of these interactions because Twsg1-/- mice manifest HPE with a low penetrance of about 17%, which increases to 100% after exposure to subteratogenic doses of the retinoic acid (RA). The objective of this study is to characterize the mechanisms of increased susceptibility of TWSG1-deficient mice to RA-induced HPE. The central hypothesis is that dysregulation of bone morphogenetic protein (BMP) signaling in Twsg1 mutants reduces an apoptotic threshold, sensitizing the embryos to teratogenic effects of RA. Disrupting apoptotic pathways would be expected to be embryo-protective. The rationale for using this model is that environmental factors, unlike genetic aberrations, are modifiable in humans as long as the underlying mechanisms can be identified. Based on our preliminary data, the central hypothesis will be tested by pursuing three specific aims: 1) to examine the effects of in utero RA exposure on the molecular program that governs neural and midline facial development in Twsg1 mutant embryos;2) to examine the impact of RA exposure on BMP signaling and cellular processes underlying the HPE phenotype in Twsg1 mutant embryos;3) to understand the role of oxidative stress and p53 activation in mediating BMP/RA effects and their potential as targets for HPE prevention. The proposed research presents a novel concept that the BMP pathway may regulate embryonic susceptibility to environmental insults, such as RA. In addition, this study begins to address the role of p53 signaling in development, which is currently poorly understood. Finally, the preventive interventions that this project seeks to develop may have an impact on the current clinical practice. The expected outcomes of this study are: 1) elucidation of the mechanisms of gene-environment interactions in the pathogenesis of HPE, specifically how mutations with low penetrance can sensitize the embryos to environmental teratogens;2) improved understanding of the interactions between BMP and RA signaling;3) enhanced knowledge about the roles of the oxidative stress and p53 activation in HPE;and 4) establishment of a model for testing preventive interventions for embryonic teratogens. Such results are expected to have an important positive impact on prevention of craniofacial defects.
Funding Period: 2013-09-18 - 2014-08-31
more information: NIH RePORT

Detail Information

Research Grants30

  1. The Shelf Live Evaluation of Investigational Dosage Forms
    Jonathan White; Fiscal Year: 2013
    ..This contract is essential for continued assurance of the quality of drugs undergoing clinical investigation for different types of cancer by Cancer Therapeutics Evaluation Program. ..
  2. Interactions between Shh pathway regulators and fetal alcohol exposure in mice
    Robert S Krauss; Fiscal Year: 2013
    ..Such information may have important public health impact and could ultimately aid in the counseling of mutation carriers. ..
  3. The Neurobiology of Social Decision-Making
    Ralph Adolphs; Fiscal Year: 2013
    ..abstract_text> ..
  4. Midface and Upper Airway in Craniosynostosis
    JOAN THERESE RICHTSMEIER; Fiscal Year: 2013
    ....
  5. Imprinting a Connectome: Developmental Circuit Approach to Mental Illness
    Takao K Hensch; Fiscal Year: 2013
    ..Our collective goal is to establish a paradigm for the systematic dissection of developmental 'connectopathies,'which should inspire novel circuit-based therapies for mental illness. ..
  6. University of Maryland Greenebaum Cancer Center Support Grant
    Kevin J Cullen; Fiscal Year: 2013
    ..Reflecting our remarkable and continued growth, UMGCC seeks to renew its CCSG to enhance and expand its efforts in high-quality and clinically relevant cancer research. ..
  7. DF/HCC SPORE in Prostate Cancer
    Philip W Kantoff; Fiscal Year: 2013
    ..abstract_text> ..
  8. MOLECULAR BASIS OF TISSUE INTERACTIONS THAT REGULATE CRANIOFACIAL DEVELOPMENT
    Ralph S Marcucio; Fiscal Year: 2013
    ....
  9. Program Project: GENE MUTATION AND RESCUE IN HUMAN DIAPHRAGMATIC HERNIA
    Patricia K Donahoe; Fiscal Year: 2013
    ..Further, the methods devised for this study of CDH may have broader implications across other congenital anomalies. ..
  10. Function of Toll-Like Receptors Throughout Gestation
    GIL G MOR; Fiscal Year: 2013
    ....
  11. The role of continuous phenotypic variation in structural defects of the face
    Ralph S Marcucio; Fiscal Year: 2013
    ..This basic research will help develop metrics for better in utero diagnostics and eventual treatments of structural birth defects of the face. ..
  12. THE ROLE OF AP-2 IN CRANIOFACIAL DEVELOPMENT
    Trevor J Williams; Fiscal Year: 2013
    ....
  13. Alzheimer's Disease Research Center
    Douglas R Galasko; Fiscal Year: 2013
    ..It will provide an environment and core resources to enhance research, foster professional and community training, and coordinate interdisciplinary research. ..
  14. Imaging and mechanistic analyses of face-brain dysmorphology in a CLP model
    Robert Lipinski; Fiscal Year: 2013
    ..abstract_text> ..
  15. Wnt Signaling in Craniofacial Developmental Disorders
    Chengji Zhou; Fiscal Year: 2013
    ....
  16. EPIDEMIOLOGY OF ALCOHOL PROBLEMS
    Thomas K Greenfield; Fiscal Year: 2013
    ..We plan to build research capacity in the Center and other organizations, enhance careers of new investigators, and make key findings accessible to researchers, policy makers, practitioners, and the public. ..
  17. Jules Stein Eye Institute Core Grant for Vision Research
    Wayne L Hubbell; Fiscal Year: 2013
    ..Support in the form of the Core grant is requested to maintain these Modules through instrument service contracts, and to provide necessary personnel support to assist and train users and provide routine maintenance. ..
  18. Expanding Excellence in Developmental Biology in Oklahoma
    Linda F Thompson; Fiscal Year: 2013
    ..abstract_text> ..
  19. ENDOTHELIN CONTROL OF RENAL HEMODYNAMIC AND EXCRETORY FUNCTION
    David M Pollock; Fiscal Year: 2013
    ..In particular, this Program will investigate a full range of mechanisms that control ET-1 release and receptor specific actions in order to provide clinically relevant information. ..
  20. Enviromental Exposures, Host Factors and Human Disease
    Frank D Gilliland; Fiscal Year: 2013
    ..The Center is poised to advance research in these areas by building on its successful approaches in facilitating cutting-edge environmental health science research. ..
  21. MMC and VICC: Partnership for Survivorship (1 of 2)
    Maureen Sanderson; Fiscal Year: 2013
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  22. COBRE for Skeletal Health and Repair
    Qian Chen; Fiscal Year: 2013
    ..This multidisciplinary approach is absolutely necessary to develop translational strategies for prevention and treatment of skeletal joint diseases. ..