Brian Joseph Cox- PhD
- Professor (Assistant) at University of Toronto
Brian Joseph Cox
- PhD
- Professor (Assistant) at University of Toronto
About
123
Publications
29,474
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5,628
Citations
Introduction
Current institution
Additional affiliations
February 2012 - present
September 1998 - August 2001
Affinium Pharmaceuticals
Position
- Senior Researcher
Description
- Ran mass spectrometry core and RnD. Protein-protein interactions studies and support for structural biology group.
August 2007 - December 2011
Publications
Publications (123)
Preeclampsia (PE) is a life-threatening hypertensive pathology of pregnancy affecting 3-5% of all pregnancies. To date, PE has no cure, early detection markers, or effective treatments short of the removal of what is thought to be the causative organ, the placenta, which may necessitate a preterm delivery. Additionally, numerous small placental mic...
The advent of reprogramming and its impact on stem cell biology has renewed interest in lineage restriction in mammalian embryos, the source of embryonic (ES), epiblast (EpiSC), trophoblast (TS), and extraembryonic endoderm (XEN) stem cell lineages. Isolation of specific cell types during stem cell differentiation and reprogramming, and also direct...
Preeclampsia (PE) adversely impacts ~5% of pregnancies. Despite extensive research, no consistent biomarkers or cures have emerged, suggesting that different molecular mechanisms may cause clinically similar disease. To address this, we undertook a proteomics study with three main goals: (1) to identify a panel of cell surface markers that distingu...
The mouse blastocyst and stem cells derived from its tissue lineages provide a unique genetic system for examining the establishment and loss of pluripotency. The transcription factor Cdx2 plays a central role by repressing pluripotency genes, such as Oct4, and promoting extraembryonic trophoblast fate at the blastocyst stage. However, genetic evid...
Placental abnormalities are associated with two of the most common and serious complications of human pregnancy, maternal preeclampsia (PE) and fetal intrauterine growth restriction (IUGR), each disorder affecting approximately 5% of all pregnancies. An important question for the use of the mouse as a model for studying human disease is the degree...
Background:
The influence of genetics on variation in DNA methylation (DNAme) is well documented. Yet confounding from population stratification is often unaccounted for in DNAme association studies. Existing approaches to address confounding by population stratification using DNAme data may not generalize to populations or tissues outside those i...
Objectives:
The incretin hormone glucagon-like peptide-1 (GLP-1) is secreted from intestinal L-cells upon nutrient intake. While recent evidence has shown that GLP-1 is released in a circadian manner in rats, whether this occurs in mice and if this pattern is regulated by the circadian clock remain to be elucidated. Furthermore, although circadian...
Statistically, patients with severe pregnancy complications are at risk of recurrent complications, but it is less understood if patients present with similar or different placental pathologies in subsequent pregnancies. In this case report, we describe 2 consecutive adverse pregnancies in the same woman 4 years apart. The first pregnancy was diagn...
Our prior work investigating the heterogeneity of preeclampsia identified multiple placental subtypes of this disorder, including a "canonical" group with maternal vascular malperfusion and an "immunological" group with signs of allograft rejection. Here, we perform a pilot immunohistochemistry study to investigate if an increase in infiltrating ma...
Omics technologies promised improved biomarker discovery for precision medicine. The foremost problem of discovered biomarkers is irreproducibility between patient cohorts. From a data analytics perspective, the main reason for these failures is bias in statistical approaches and overfitting resulting from batch effects and confounding factors. The...
Background: The influence of genetics on variation in DNA methylation (DNAme) is well documented. Yet confounding from population stratification is often unaccounted for in DNAme association studies. Existing approaches to address confounding by population stratification using DNAme data may not generalize to populations or tissues outside those in...
Aims/hypothesis
Gestational diabetes mellitus (GDM) affects up to 20% of pregnancies, and almost half of the women affected progress to type 2 diabetes later in life, making GDM the most significant risk factor for the development of future type 2 diabetes. An accurate prediction of future type 2 diabetes risk in the early postpartum period after G...
Unfortunately, the graph in Fig. 5f became misaligned during typesetting.
Tissue engineering using cardiomyocytes derived from human pluripotent stem cells holds a promise to revolutionize drug discovery, but only if limitations related to cardiac chamber specification and platform versatility can be overcome. We describe here a scalable tissue-cultivation platform that is cell source agnostic and enables drug testing un...
Introduction:
The human placenta is accessible in early developmental stages and affords a unique opportunity to investigate human organogenesis and the dynamics of transitory cell populations in human placenta development.
Methods:
The cell surface proteomic profile of early trophoblast cells of first trimester human placentas was quantified us...
Background:
Infants born small for gestational age because of pathologic placenta-mediated fetal growth restriction can be difficult to distinguish from those who are constitutionally small. Additionally, even among fetal growth-restricted pregnancies with evident placental disease, considerable heterogeneity in clinical outcomes and long-term con...
Background:
Preeclampsia (PE) is a life-threatening disorder of pregnancy, demonstrating a high degree of heterogeneity in clinical features such as presentation, disease severity and outcomes. This heterogeneity suggests distinct pathophysiological mechanisms may be driving the placental disease underlying this disorder. Our group recently report...
The advent of text mining and natural text reading artificial intelligence has opened new research opportunities on the large collections of research publications available through journal and other resources. These systems have begun to identify novel connections or hypotheses due to an ability to read and extract information from more literature...
Aim
Prescription ω‐3 fatty acid ethyl ester supplements are commonly used for the treatment of dyslipidemia in humans. Recent studies show that 3‐carboxy‐4‐methyl‐5‐propyl‐2‐furanpropanoic acid (CMPF), a metabolite formed from fish oil supplementation, was able to prevent and reverse high fat diet (HFD) induced fatty liver in mice. In the present s...
A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper.
Background
Preeclampsia (PE) is a heterogeneous, hypertensive disorder of pregnancy, with no robust biomarkers or effective treatments. We hypothesized that this heterogeneity is due to the existence of multiple subtypes of PE and, in support of this hypothesis, we recently identified five clusters of placentas within a large gene expression microa...
Gastrulation initiates with the formation of the primitive streak, during which, cells of the epiblast delaminate to form the mesoderm and definitive endoderm. At this stage, the pluripotent cell population of the epiblast undergoes very rapid proliferation and extensive epigenetic programming. Here we show that Fam208a, a new epigenetic modifier,...
Genomic imprinting is essential for normal placental and fetal growth. One theory to explain the evolution of imprinting is the kinship theory (KT), which predicts that genes that are paternally expressed will promote fetal growth, whereas maternally expressed genes will suppress growth. We investigated the expression of imprinted genes using micro...
Placental health is a key component to a successful pregnancy. Placental insufficiency (PI), inadequate nutrient delivery to the fetus, is associated with preeclampsia (PE), a maternal hypertensive disorder, and intrauterine growth restriction (IUGR), pathologically poor fetal growth. PI is more common in early-onset PE (EOPE) than late-onset PE (L...
Movie S1. Self-Organization of Stage 3 Cells into Epithelial Buds in Stage 4 3D Matrigel-Based Culture Conditions, Related to Figure 1
Images were taken every 6 hr for a total of 8 days. Acquired using a Nikon BioStation CT. Scale bar, 100 μm.
Introduction
The placenta demonstrates a recognized sequence of histomorphologic maturation throughout pregnancy, and in some cases, shows abnormally advanced (AVM) or delayed (DVM) villous maturation. While AVM and DVM have important clinical implications, it is unknown whether they truly represent a state of accelerated/delayed normal maturation...
Intestinal organoids derived from human pluripotent stem cells (hPSCs) are valuable in vitro research models that enable simplified access to human gastrointestinal tissues. Here, we report the in vitro generation of enterospheres (hEnS) from hPSC-derived gastrointestinal epithelial precursors. hEnS are cystic spheroids with a simple uniform struct...
Placental health is a key component to healthy pregnancy. Placental insufficiency (PI), inadequate nutrient delivery to the fetus, is associated with preeclampsia (PE), a maternal hypertensive disorder, and intrauterine growth restriction (IUGR), pathologically poor fetal growth. PI is more common in early-onset PE (EOPE) than late-onset PE (LOPE)....
The first cell fate choice of the preimplantation embryo generates the extraembryonic trophoblast and embryonic epiblast lineages. Embryonic stem cells (ESCs) and trophoblast stem cells (TSCs) can be utilized to investigate molecular mechanisms of this first cell fate decision. It has been established that ESCs can be induced to acquire trophoblast...
The placenta is composed of two lineages: the trophoblast and mesoderm. While morphological assessment of the placenta has highlighted major cell types and developmental structures, the human placenta is relatively unexplained on a molecular level. Current molecular analysis of the placenta has largely been confined to assessing whole organs that i...
Gestational diabetes (GDM) affects 3-14% of pregnancies, 20-50% of which progress to T2D within 5 years. This study sought to develop a metabolomics signature to predict the transition from GDM to T2D. A prospective cohort of 1035 women with GDM pregnancy were enrolled at 6-9 weeks post-partum (baseline) and screened for T2D annually for 2 years. O...
Preeclampsia (PE) is a complex, hypertensive disorder of pregnancy, demonstrating considerable variability in maternal symptoms and fetal outcomes. Unfortunately, prior research has not accounted for this variability, resulting in a lack of robust biomarkers and effective treatments for PE. Here, we created a large (N=330) clinically relevant human...
Prediabetes, a state of mild glucose intolerance, can persist for years before a sudden decline in beta cell function and rapid deterioration to overt diabetes. The mechanism underlying this tipping point of beta cell dysfunction remains unknown. Here, the furan fatty acid metabolite CMPF was evaluated in a prospective cohort. Those who developed o...
Elf5 is a transcription factor with pivotal roles in the trophoblast compartment, where it reinforces a trophoblast stem cell (TSC)-specific transcriptional circuit. However, Elf5 is also present in differentiating trophoblast cells that have ceased to express other TSC genes such as Cdx2 and Eomes. In the present study, we aimed to elucidate the c...
The placenta is the essential organ of mammalian pregnancy and errors in its development and function are associated with a wide range of human pathologies of pregnancy. Genome sequencing has led to methods for investigation of the transcriptome (all expressed RNA species) using microarrays and next-generation sequencing, and implementation of thes...
Atrial fibrillation (AF) is the most common supraventricular arrhythmia that, for unknown reasons, is linked to intense endurance exercise. Our studies reveal that 6 weeks of swimming or treadmill exercise improves heart pump function and reduces heart-rates. Exercise also increases vulnerability to AF in association with inflammation, fibrosis, in...
The advent of genome-wide analysis has brought exciting new concepts to the field of biology, development, and disease. These techniques and their associated data sets also come with great challenges in terms of application, analysis, and interpretation. This chapter describes some of these techniques in general language and presents their applicat...
Background
Endoplasmic reticulum (ER) resident protein 44 (ERp44) is a member of the protein disulfide isomerase family, is induced during ER stress, and may be involved in regulating Ca2+ homeostasis. However, the role of ERp44 in cardiac development and function is unknown. The aim of this study was to investigate the role of ERp44 in cardiac dev...
Preeclampsia is a relatively common hypertensive disorder of pregnancy that remains a high cause of maternal and fetal death due to the lack of early detection and treatment options. While the etiology is unclear, the placenta is the origin of preeclampsia and it releases factors into maternal circulation to induce systemic endothelial dysfunction....
In mouse and humans, the X-chromosomal Porcupine homolog (Porcn) gene is required for the acylation and secretion of all 19 Wnt ligands, thus representing a bottleneck in the secretion of Wnt ligands. In humans, mutations in PORCN cause the X-linked dominant syndrome Focal Dermal Hypoplasia (FDH, OMIM#305600). This disorder is characterized by ecto...
In mice and humans the X-chromosomal porcupine homolog (Porcn) gene is required for the acylation and secretion of all 19 Wnt ligands and thus represents a bottleneck for all Wnt signaling. We have generated a mouse line carrying a floxed allele for Porcn and used zygotic, oocyte-specific and visceral endoderm-specific deletions to investigate embr...
The placental microvasculature is essential for efficient transfer of gases, nutrients and waste between the mother and fetus. Microvascular hypoplasia of the terminal villi is a common pathology in severe Intra Uterine Growth Restriction (IUGR). We used novel methods to obtain placental micro-vascular endothelial cells (PlMEC) from preterm control...
The node and notochord are key tissues required for patterning of the vertebrate body plan. Understanding the gene regulatory network that drives their formation and function is therefore important. Foxa2 is a key transcription factor at the top of this genetic hierarchy and finding its targets will help us to better understand node and notochord d...
Wnt signaling plays important roles in development and disease. The X-chromosomal Porcupine homolog gene (Porcn) encodes an evolutionary conserved member of the membrane bound O-acyl transferase (MBOAT) superfamily that has been shown to be required for the palmitoylation and secretion of Wnt3a, a mechanism that has been suggested to be conserved f...
Renal dysplasia, defined by defective ureteric branching morphogenesis and nephrogenesis, is the major cause of renal failure in infants and children. Here, we define a pathogenic role for a β-catenin-activated genetic pathway in murine renal dysplasia. Stabilization of β-catenin in the ureteric cell lineage before the onset of kidney development i...
Mutational screens are an effective means used in the functional annotation of a genome. We present a method for a mutational screen of the mouse X chromosome using gene trap technologies. This method has the potential to screen all of the genes on the X chromosome without establishing mutant animals, as all gene-trapped embryonic stem (ES) cell li...
A unique property of the mammalian embryo is that stem cells can be derived from its early tissue lineages. These lineages will give rise to the fetus as well as essential extraembryonic tissues. Understanding how chromatin regulation participates in establishment of these lineages in the embryo and their derived stem cells provides insight that wi...
Supplementary tables SI-VIII
Materials & Methods and Supplementary figures S1–4
A report from the Keystone Symposium on Molecular and Cellular Biology, 'Omics Meets Cell Biology', Breckenridge, Colorado, 25-30 January, 2009.
The Spemann/Mangold organizer is a transient tissue critical for patterning the gastrula stage vertebrate embryo and formation of the three germ layers. Despite its important role during development, there are still relatively few genes with specific expression in the organizer and its derivatives. Foxa2 is a forkhead transcription factor that is a...
Analysis of Foxa expression data by Heiko Lickert. Report and details of Affymetrix MOE430v2 GeneChip data analysis.
Supplementary materials and methods: page 2 abbreviations used in supplementary tables. Page 3 Primers for generating IVT Templates. Page 4 Q-PCR methods. Page 5 Q-PCR primers. Page 6 Gene Ontology analysis using GOFFA. Page 7 oPOSSUM methods Page 8 SynoR methods.
Supplementary Figures. Additional whole mount in situ images organized alphabetically by current MGI gene symbol.
Supplementary Table 5. Gene Ontology (GO) terms significantly enriched (p ≤ 0.01) among genes expressed in the secondary tissues affected in Foxa2 mutants.
Supplementary Table 7. oPOSSUM output: putative target genes with conserved Foxa2 binding motifs.
Supplementary Table 1. List of genes screened by whole mount in situ hybridization that had a ≥ 1.5 fold decrease in Foxa2 mutants, as detected by the Affymetrix U74Av2 array.
Supplementary Table 2. List of genes screened by whole mount in situ hybridization that did not meet the 1.5 fold decrease threshold in Foxa2 mutants, as detected by the Affymetrix U74Av2 array.
Supplementary Table 4. Gene Ontology (GO) terms significantly enriched (p ≤ 0.01) among genes expressed in the primary tissues affected in Foxa2 mutants.
Supplementary Table 9. Summary of conserved Foxa2 and T binding motif predictions around putative Foxa2 target genes.
Supplementary Table 3. List of genes screened by whole mount in situ hybridization that were significantly reduced in Foxa2 mutants, as detected by the Affymetrix MOE430v2 array.
Supplementary Table 8. oPOSSUM output: putative target genes with conserved Brachyury/T binding motifs.
Starting material for Foxa2 expression profiling. Details of the numbers and stages of embryos collected for the screen.
Supplementary Table 6. oPOSSUM output: TF motifs identified in promoters of genes reduced in Foxa2 mutants and expressed in regions of Foxa2 activity.
Questions
Questions (4)
I participated in the workshop on "Creating a placental research network" at IFPA 2013. We are going forward with making a global network. We are at an information gathering stage. If you would like to participate or know someone who might, please have them contact me. We will send out a survey followed by a web launch with links to resources and networks of placental researchers and groups.
