Director of Medical Education and Director of Neonatology Fellowship Training Program
Mary Ann Swetland Environmental Health Center and Division of Neonatology Rainbow Babies & Children's Hospital
Case Western Reserve University
RB & C
L1 cell adhesion molecule and fetal alcohol syndrome: The major research focus in my laboratory is the effect of ethanol on the cell adhesion molecule, L1. The neuroanatomy of patients with defects in L1 is similar to that of patients with fetal alcohol syndrome, suggesting a role for L1 in the pathogenesis of the central nervous system abnormalities found in these patients. L1 is a transmembrane glycoprotein that promotes and regulates neuronal adhesion and neurite outgrowth by activation of signaling cascades and clathrin-dependent endocytosis. L1 mediates adhesion by binding homophilically to another L1 on an apposing neuron. Adhesion generates signal transduction involving src and MAP kinases, and possibly the fibroblast growth factor receptor. Inhibition of endocytosis blocks MAP kinase activation, and inhibition of MAP kinase inhibits neurite outgrowth. Interestingly, we found that L1 adhesion was unaffected by ethanol, while L1 mediated neurite outgrowth was inhibited at low physiologic concentrations of ethanol. We are currently investigating the effects of ethanol on L1 signal activation, and endocytosis.
Cerebral palsy (CP) is one of the major neurodevelopmental handicaps of premature infants, yet its etiology remains poorly understood. Currently, severe cranial ultrasound abnormalities are the best predictor for the development of CP. However, in a recent study, 48% of preterm infants who developed CP had a normal ultrasound. To identify infants at risk for CP, better and earlier predictors are needed. CP frequently involves the corticospinal tract. The development of this tract is dependent on the expression of an axon guidance molecule L1. L1 can be detected in cerebrospinal fluid (CSF). We have found that the amount and the pattern of several high molecular weight forms of L1 are dependent on postconceptual age with large amounts of the higher molecular weight forms present in the CSF of preterm infants. We are investigating the normal and abnormal developmental pattern of these forms.
Alcohol use during pregnancy is a significant public health problem. Heavy drinking during pregnancy can cause the fetal alcohol syndrome (FAS), the leading known cause of mental retardation. In addition, drinking during pregnancy can result in a spectrum of effects: alcohol-related birth defects, alcohol-related neurodevelopmental defects and subtle deficits on a variety of behavioral, educational and psychological tests. It is estimated that 1% of all live births suffer some prenatal alcohol damage and cost society anywhere from $75 million to $9.7 billion per year. Identifying the alcohol-exposed newborn is difficult. Early identification of affected infants is desirable to best determine effective secondary prevention strategies. We have developed a technique to measure ethanol metabolites in meconium, the first stools passed by newborns. The amount of these metabolites is highly associated with maternal self-reported drinking. A cutoff value for these metabolites determined in an abstaining population was found to identify infants in a study population who scored significantly lower on the Bayley Test of Infant Intelligence. We are currently developing an ovine animal model to further validate this test, as well as extending these observations in study populations in South Africa, Chile, Utah and Jordan.
|Ph.D. Student / Postdoc||Present Position|
|Dr. Nataly Yeaney||Assistant Professor, Pediatrics|
|Dr. Mary Nock||Assistant Professor, Pediatrics|