Christopher J. Ward, MBChB, PhD

Professional Background

Dr. Christopher J. Ward was born and raised in Scotland and received his medical training at Edinburgh University qualifying in 1986. He then did a PhD in immunology at the University of Birmingham, England before joining the laboratory of Prof Peter Harris in Oxford. Dr. Ward was closely involved in the positional cloning of the tuberous sclerosis type 2 (TSC2) gene and the polycystic kidney disease type 1 (PKD1) gene and developed a range of antibody reagents designed to detect the product of the PKD1 gene, polycystin-1. In 2000, Drs. Ward and Harris moved to the Mayo Clinic and identified the gene for autosomal recessive polycystic kidney disease (PKHD1) using the pck rat model which is orthologous to PKHD1. Again, Dr. Ward developed antibody reagents to the product of PKHD1, fibrocystin, as well as generating two mouse models of the disease. In collaboration with Dr. Marie Hogan, Dr. Ward showed that extracellular vesicles contain the products of the three major human PKD genes and did an extensive proteomic analysis on these. This survey then lead to the development of a test for ADPKD and to the formulation of the exosome cilium interaction theory (ECIT). This idea suggests that extracellular vesicles, released into the urine flow, can transmit a `urocrine’ signal by interacting with primary cilia and that polycystic kidney disease is due to a failure of this novel signaling pathway.

• MBChB, General Medicine, Edinburgh, Edinburgh, Scotland
• Post Doctoral Fellowship, Genetics, Weatherall Institute of Molecular Medicine (Institute of Molecular Medicine (IMM)), Oxford, England
• Other, Genetics, Weatherall Institute of Molecular Medicine and Mayo Clinic, Oxford, England

Research

Overview

Dr. Christopher J Ward's major interest is in the pathophysiology of autosomal dominant polycystic kidney disease (ADPKD) and in particular the differences in disease severity observed with affected pedigrees. The protein products of the three major human polycystic kidney disease genes, polycystin-1 product of PKD1, polycystin-2 product of PKD2 and fibrocystin product of PKHD1 are present on 100nm diameter extracellular vesicles shed in human urine. These can be used as a source of the proteins for the analysis of the polyprotein complexes made by the association of these three proteins. Furthermore, urinary extracellular vesicles have been used to develop a test for the severity of ADPKD as the level of polycystin-1 correlates inversely with disease severity. Extracellular vesicles have also been used to identify potential extracellular ligands for polycystin-1.
Dr.Ward showed that splicing in human polycystin-1 is inefficient with 30-60% of transcripts mis-splicing over introns 21 and 22 of the human but not the mouse PKD1 gene. This is because introns 21 and 22 have long CT rich tracts of 2.5kb and 600bp respectively in the case of the human, no CT tracts are observed in the mouse. Dr. Ward showed that up to 60% of PKD1 transcripts terminate early producing a shorter, presumably antagonistic form of polycystin-1 termed Trunc_PC1. Dr. Ward hypothesizes that the poor splicing efficiency decreases the level of functional full length polycystin-1 and increases the level of Trunc_PC1. In the context of a germline PKD1 mutation the level of aberrant splicing controls the amount of functional polycystin-1 and thus disease severity. This is reflected in the inverse association between full length extracellular vesicle polycystin-1 and kidney size. One therapeutic approach would be to enhance the amount of full length polycystin-1 by blocking the aberrant splicing events around introns 21 and 22 using antisense oligonucleotides (ASOs).