John Kingdom

Areas of Expertise: Placental Development and Pathology Ultrasound Imaging of the Placenta Molecular pathology of preeclampsia/IUGR Non-anticoagulant actions of Heparin Screening for “Placental Insufficiency” disorders Invasive placentation Research Interests: All my research efforts are focused on aspects of placental development and pathology. My clinical research interests focus on screening and prevention of placental complications of pregnancy. These interests focus on placental pathology and include an interest in invasive placentation (placenta accrete). My basic science interests focus on; the molecular control of syncytio-trophoblast formation and function, the interactions of the placenta with heparin and the molecular pathology of the placenta in pregnancies complicated by severe pre-eclampsia and/or severe intrauterine growth restriction. Keywords: Development, Doppler, Hemodynamics, Heparin, Molecular Biology, Pathology, Placenta, Placental Ultrasound, Pre-eclampsia, Trophoblast Detailed Description: Severe placental dysfunction is characterized by reduced/unstable utero-placental blood flow (from the mother to the inter-villous space of the placenta) and defective elaboration of the floating (chorionic) villi that extract nutrients and oxygen for the developing fetus. The histopathology includes variable degrees of; vasculopathy of the decidual portions of the utero-placental arteries, arrested feto-placental angiogenesis and defects in the outer syncytiotrophoblast (SCT) layer covering the floating villi. Secondary pathologies (hemorrhage, infarction, maternally-derived inflammation) compound the initial developmental abnormalities of the extra-villous and villous trophoblast. My laboratory at the Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, focuses on the physiologic control mechanisms controlling SCT formation, which is a balance between cytotrophoblast proliferation and cell—syncytium fusion of post-mitotic differentiated cells, and the communication pathways (involving soluble proteins and micro-particles), between the syncytiotrophoblast and the maternal arterial vasculature. The two major clinical manifestations of severe placental dysfunction in humans are severe forms of pre-eclampsia [sPE] and IUGR. sPE refers to hypertension accompanied by multi-organ dysfunction, especially renal injury; it is a systemic vasculopathy characterized by excess secretion, by the SCT layer of the placenta, of splice-variant anti-angiogenic proteins including sFlt1 and by the excess production of an array of micro-particles, especially exosomes that transport micro-RNAs in a protected manner around the body. Serum from women with sPE arrests in-vitro angiogenesis but is reversed by pre-exposure of placental villi to heparin. In human trials, heparin reduces the risk of recurrent sPE, though curiously this is accompanied by an elevation in sFlt1. Our current hypothesis, funded by a March 2013 competition CIHR grant, is that heparin exerts complex non-anti-coagulant actions – specifically heparin may promote re-formation of the SCT where expression of nitric oxide synthase and hemoxygenase may lead to restoration of the production of vasodilator gases (NO and CO) that in part mediate systemic vasodilation of normal pregnancy. Heparin may also interfere with the release or entry, of exosomes into target cells. My laboratory is integrated within the 6th floor reproductive sciences program at the Lunenfeld directed by Dr. Stephen Lye. The heparin research program has an in-vivo mouse aim, which is conducted in collaboration with Dr. John Sled (and until 2014, Dr S Lee Adamson). The human trophoblast biology research collaborates with Main Campus (Dr. Brian Cox, PhD, Department of Physiology) for his expertise in systems biology and with Dr. Jeff Wrana (also at LTRI) for his expertise in micro-particle biology and miRNA sequencing. These basic research programs are integrated with the Placenta Clinic at Mount Sinai Hospital (www.mountsinai.on.ca/care/placenta-clinic) where my clinical research program focuses on screening, diagnosis and management of pregnancies at risk of a variety of placental complications. This program, together with the larger Maternal-Fetal Medicine Division, manages a large number of pregnancies with these problems. At delivery, our Biobank team samples the delivered placenta using protocols for future molecular pathology, genetics and epigenetics studies on a case-control basis. This program is integrated with our specialty perinatal pathology program (Dr. Sarah Keating, MD) for correlative research studies. A variety of clinical and translational research questions are pursued by trainees in this environment. The “placental health study in Nulliparous Women” is a recently-completed prospective two-year screening program funded by MSH-UHN AFP Innovation fund,, in 1100 women at Mount Sinai Hospital. The program is evaluating the ability of clinical risk scoring, blood tests, and ultrasound imaging of the placenta, to identify women at most risk of sPE and/or IUGR/stillbirth. Our current work in this area is examining the role of advanced 3D ultrasound imaging methods to refine the “placental morphology” component, together with the incorporation of pro-/anti-angiogenic markers (sflt1 and PlGF) to maximize the precision of our screening algorithm. The placenta clinic support a comprehensive program of research at SickKids investigating how the fetal heart protects the fetal brain by ensuring that it is properly oxygenated, and in turn how these regulatory mechanism can fail in both IUGR pregnancies and in pregnancies where the fetus is found to have complex congenital heart disease. The placenta clinic interacts with the Department of Cardiology at Mount Sinai Hospital to understand the in-vivo hemodynamic actions of heparin that may promote optimal vascular function to reduce the risk of severe pre-eclampsia in women at high risk, based on placental function testing ion the 16-22 week window.