Indiana University School of Medicine

Simon J. Conway, PhDResearchers

Simon J. Conway, PhD, FAHA Professor, Department of Pediatrics

Professor: Department of Pediatrics

Clinical Section: Neonatal-Perinatal Medicine

Basic Science Joint Appointment: Biochemistry and Molecular Biology, Anatomy and Cell Biology, Medical and Molecular Genetics

Program Leader: Developmental Biology and Neonatal Medicine

PhD: Mammalian Development Unit, Medical Research Council (UK), University College London, England (1993)

Postdoctoral Fellowship: Institute of Child Health, Great Ormond Street Children's Hospital, England

E-mail: siconway@iupui.edu

Pub Med Search

Current Research Interests:

Our research has a single common aim - to understand congenital abnormality pathogenesis and prevent in utero lethality.

Research:

We principally focus on congenital cardiovascular defects, as they are the #1 birth defect and each year over 30,000 babies in USA are born with a defective cardiovascular system (www.nhlbi.nih.gov). Significantly, the heart is the first organ to develop in the mammalian embryo and remarkably it is required to function even before it is fully formed. We study the underlying causes of outflow tract and valvular heart defects, which result from a failure of the aorta and pulmonary trunks to become separate blood vessels and associated outflow tract endocardial cushion/valvular remodeling anomalies. Lack of outflow tract septation often results in lethality secondary to respiratory failure as there is inappropriate mixing of oxygenated and de-oxygenated circulations postnatally. Similarly, valvular insufficiency can also result in postnatal lethality due to an inability to maintain a unidirectional bloodflow. Using transgenic over-expressor, targeted systemic and Cre/loxP conditional knockout mice models, we are investigating when cardiovascular development first goes wrong (both in utero and postnatally), identifying the cell lineages responsible (using various reporter lineage mapping mice), genetically ablating (via diphtheria toxin-A), assessing resultant cardiac function (via echocardiography) and varying responses to myocardial insults, and then attempting to correct and/or alleviate the various structural and myocardial dysfunction anomalies observed. If these experimentally-induced congenital defects can be prevented and/or nullified in genetically-defined mutant mouse models, we then hope to apply the knowledge gained to help engineer potential treatments for neonatal patients.

Ongoing projects include:

  • Pax3 transcription factor systemic, hypomorphic and conditional knockout mouse mutants are being used to assess the cell autonomous requirement of the cardiac neural crest during outflow septation and the trunk neural crest within the development of the sympathetic nervous system.
  • In collaboration with the Ingram, Clapp and Yang labs (Developmental Biology & Neonatal Medicine Program), we are defining the aberrant signaling networks in Neurofibromatosis-deficient neural crest, endothelial and vascular smooth muscle lineages and have developed in vivo murine knockout/bone marrow transplantation models of NF1 disease that closely recapitulate the human phenotype. Currently, we are using a new mouse model and several state-of-the-art lineage-restricted Cre/loxP lines for genetic ablation of Nf1 specifically in bone marrow-derived cells to indentify the primary effectors of Nf1+/- disease.
  • Periostin knockout, promoter reporter and Cre-recombinase expressing mice are being used to determine the role of secreted Periostin adhesion protein during establishment of the embryonic heart’s skeleton and morphogenesis of the cardiac fibroblast lineage. In parallel, TgfbI knockout mice (which are another fasciclin-containing adhesion factor related to Periostin) are being used to assess genetic redundancy. Both Periostin and Tgfbi are TGFß- responsive targets within the tumor microenvironment and these compound mouse mutants provide useful models to examine the role of the ECM during metastasis (IU Simon Cancer Center Member).
  • We generated a Smad7 inducible over-expressor transgenic mouse, to model the inhibitory effects of attenuated TGFß/Bmp superfamily signaling during neural crest migration and endocardial cushion maturation to septate the outflow tract and form the fibrous valve leaflets. This novel model is now being employed to examine lineage-restricted effects upon in utero and post-natal cardiovascular myocyte and endothelial cells.
  • To examine the practical consequences of altered cardiac function, we generated Sodium Calcium Exchanger-1 knockouts that fail to initiate a heartbeat. This mouse line represents a unique model to investigate the consequences of absent heartbeat on determination of cardiac form vs. function and requirement of bloodflow during vascular remodeling and onset of hematopoiesis.

Dr. Conway Laboratory