Row 1: D Elder, N Crimmins
Row 2: N Yayah Jones, I Gutmark-Little, A Sanghavi Shah
Row 3: M Rutter, P Backeljauw, S Lawson
Row 4: D Klein, L Dolan, J Katz
Turner Syndrome Research
The Turner Syndrome Center has investigated cardiovascular anomalies in Turner syndrome (TS) patients by cardiac MRI, including aortic abnormalities and partial anomalous pulmonary venous return (PAPVR). The prevalence of PAPVR was found to be 18 percent. Six of the newly diagnosed patients had not been diagnosed by echocardiogram. Another study found the prevalence of hypertension in TS girls to be under-recognized. More attention should be given to careful determination, interpretation and follow-up of blood pressure monitoring in TS girls, including a recommendation to manually perform all blood pressure measurements in TS girls . A prospective study comparing the prevalence of vasculopathy in TS patients showed evidence of increased arterial stiffness. This puts TS girls at greater risk for cardiovascular disease later in life. As a next step, measurements of TS-specific comorbidities will be evaluated in an attempt to determine the specific at-risk TS population. These studies underscore the importance of a multidisciplinary approach to TS care, together with the development of a large patient database. New studies being developed will focus on further evaluation of large vessel disease, assessment of airway dysfunction and studies looking at abnormalities of glucose metabolism.
Placental Development in Normal and Pathologic Pregnancies
Many pathologic conditions of pregnancy that result in infant morbidity and mortality, such as preeclampsia and intrauterine growth retardation (IUGR), are characterized by abnormal placental development. Research by Stuart Handwerger, MD, and his colleagues examines the roles for protein hormones, transcription factors and other signaling molecules in the development of normal and pathologic placentas. They postulate that a better understanding of the factors that regulate placental growth and development may lead to the discovery of therapeutic modalities that prevent or correct abnormal placental development and that improve fetal outcome. Their recent investigations have shown that placental development is critically dependent upon the transcription factors TFAP2A and NR2F2, both of which modulate cell structure, cell growth and hormone expression. The mRNA and protein levels of both transcription factors were shown to increase markedly during placental development; silencing the expression of either transcription factor was observed to markedly inhibit development. NR2F2 and TFAP2A were shown to form a positive feedback loop in which NR2F2 induces TFAP2A expression and TFAP2A in turn induces NR2F2. NR2F2 also potentiated the effect of retinoic acid on TFAP2A. Having demonstrated that TFAP2A and NR2F2 are critical for normal placental development, Handwerger, in collaboration with Jerzy Stanek, MD, PhD, and Rachel Sheridan, MD, of the Division of Pathology, recently observed by immunohistochemical analyses that TFAP2A protein levels in preeclampsia and IUGR placentas are markedly decreased compared to levels in gestational age-matched control placentas. Similar NR2F2 studies have not as yet been completed. Since these studies suggest that the abnormal placental development and function in preeclampsia and IUGR may be due, at least in part, to abnormalities in TFAP2A (and possibly NR2F2) expression, subsequent studies will examine whether correcting TFAP2A (and possibly NR2F2) expression in cultures of pathologic placentas will result in normal development.
Causes and Control of Type 1 Diabetes
Our research focuses on type 1 diabetes (T1D) by using a non-obese diabetic (NOD) mouse model . During the past year, our NIH-funded work has focused mainly on three areas: the role plasmacytoid dendritic cells and natural killer T cells play in establishing an immunoregulatory environment in mice that are protected from disease; the role merocytic dendritic cells play in breaking peripheral T cell tolerance to islet cell antigen (in collaboration with Edith Janssen, PhD, in the Division of Molecular Immunology); and the potential use of small molecule inhibitors of Bcl-2 family members in targeting diabetogenic CD4+ and CD8+ T cells for specific destruction to enhance long-term tolerance and to facilitate a novel therapeutic strategy to re-establish tolerance in T1D patients (in collaboration with David Hildeman, PhD, in the Division of Immunobiology). Together these studies are designed to understand what normally controls T1D development, what underlies the basic response to beta cell antigens and, finally, what can be done to facilitate the restoration of normal beta cell function and glucose regulation in T1D patients.