A5062018673- Pancreatic function and diabetes
- Diabetes and associated disorders
- Diabetes Management and Research
- Pluripotent Stem Cells Research
- Genetics and Neurodevelopmental Disorders
- Metabolism, Diabetes, and Cancer
- Diabetes Treatment and Management
- CRISPR and Genetic Engineering
- Epigenetics and DNA Methylation
- Analog and Mixed-Signal Circuit Design
- Adipose Tissue and Metabolism
- MicroRNA in disease regulation
- Reproductive Biology and Fertility
- Diet, Metabolism, and Disease
- Reproductive System and Pregnancy
- Endoplasmic Reticulum Stress and Disease
- Pancreatic and Hepatic Oncology Research
- Histone Deacetylase Inhibitors Research
- Pancreatitis Pathology and Treatment
- Molecular Communication and Nanonetworks
- Regulation of Appetite and Obesity
- Neuroscience and Neural Engineering
- Adipokines, Inflammation, and Metabolic Diseases
- GDF15 and Related Biomarkers
- Congenital heart defects research
Stanford University
2021-2025
University of British Columbia
2013-2025
Centre for Human Genetics
2018-2024
University of Oxford
2018-2024
British Columbia Children's Hospital
2017-2022
Child and Family Research Institute
2013-2016
BC Cancer Agency
2014
Human embryonic stem cells (hESCs) are a potential unlimited source of insulin-producing β for diabetes treatment. A greater understanding how form during development will improve current hESC differentiation protocols. All pancreatic endocrine cells, including derived from Neurog3-expressing progenitors. This study characterizes the single-cell transcriptomes 6,905 mouse day (E) 15.5 and 6,626 E18.5 isolated Neurog3-Cre; Rosa26mT/mG embryos, allowing enrichment progenitors (yellow; tdTomato...
Abstract The coding variant (p.Arg192His) in the transcription factor PAX4 is associated with an altered risk for type 2 diabetes (T2D) East Asian populations. In mice, Pax4 essential beta cell formation but its role on human development and/or function unknown. Participants carrying p.His192 allele exhibited decreased pancreatic compared to homozygotes p.192Arg a cross-sectional study which we carried out intravenous glucose tolerance test and oral test. pedigree of patient young onset...
Endocrine dysfunction and diabetes can develop secondary to fibrotic diseases within the pancreas including cystic fibrosis (CF). Phenotypic shift epithelial cells has been recognised in association with pro-fibrotic signalling. We sought evidence of endocrine cell epithelial-to-mesenchymal transition CF non-CF pancreas. Post mortem pancreatic sections from 24 people 10 organ donors without or were stained for insulin/glucagon/vimentin Sirius Red Fast Green collagen distribution assessed...
Abstract Aims/hypothesis Genome-wide studies have uncovered multiple independent signals at the RREB1 locus associated with altered type 2 diabetes risk and related glycaemic traits. However, little is known about function of zinc finger transcription factor Ras-responsive element binding protein 1 (RREB1) in glucose homeostasis or how changes its expression and/or influence risk. Methods A zebrafish model lacking rreb1a rreb1b was used to study effect loss vivo. Using transcriptomic...
Cellular homeostasis requires intrinsic sensing mechanisms to temper function in the face of prolonged activity. In pancreatic β-cell, glucose is likely a physiological trigger that activates an adaptive response stimulation, thereby maintaining cellular homeostasis. Immediate early genes (IEGs) are activated as first line defense and largely responsible for transmitting environmental cue response. Here we examine regulation novel β-cell IEG, neuronal PAS domain protein 4 (Npas4). Using MIN6...
Inducible pluripotent stem cell–derived human β-like cells (BLCs) hold promise for both therapy and disease modeling, but their generation remains challenging functional analyses beyond transcriptomic morphological assessments remain limited. Here, we validate an approach using multicellular single-cell electrophysiological tools to evaluate function of BLCs from pioneer protocols that can be easily adapted more differentiated BLCs. The multi-electrode arrays (MEAs) measuring the...
Human embryonic stem cells (hESCs) have great promise as a source of unlimited transplantable for regenerative medicine. However, current progress on producing the desired cell type disease treatment has been limited due to an insufficient understanding developmental processes that govern their differentiation, well paucity tools systematically study differentiation in lab. In order overcome these limitations, cell-type reporter hESC lines will be required. Here we outline two strategies...
Transcriptional and functional cellular specialization has been described for insulin-secreting β-cells of the endocrine pancreas. However, it is not clear whether β-cell heterogeneity stable or reflects dynamic states. We investigated temporal kinetics endogenous insulin gene activity using live cell imaging, with complementary experiments FACS single-cell RNA sequencing, in from Ins2GFP knockin mice. In vivo staining analysis islets mice confirmed that at a given moment, ∼25% exhibited...
Appropriate regulation of genes that coordinate pancreas progenitor proliferation and differentiation is required for development. Here, we explore the role H3K4 methylation Trithorax group (TrxG) complexes in mediating gene expression during Disruption TrxG complex assembly, but not catalytic activity, prevented endocrine cell spheroids. In vivo loss activity PDX1+ cells increased apoptosis fraction progenitors G1 phase cycle. Pancreas were reallocated to acinar lineage, primarily at...
Identifying the transcripts which mediate genetic association signals for type 2 diabetes (T2D) is critical to understand disease mechanisms. Studies in pancreatic islets support transcription factor ZMIZ1 as a transcript underlying T2D GWAS signal, but how it influences risk unknown. β-Cell-specific Zmiz1 knockout (Zmiz1βKO) mice were generated and phenotypically characterised. Glucose homeostasis was assessed Zmiz1βKO their control littermates on chow diet (CD) high fat (HFD). Islet...
Abstract Transcriptional and functional cellular specialization has been described for insulin-secreting β-cells of the endocrine pancreas. However, it is not clear whether β-cell heterogeneity stable or reflects dynamic states. We investigated temporal kinetics endogenous insulin gene activity using live cell imaging, with complementary experiments employing FACS single RNA sequencing, in from Ins2 GFP knock-in mice. In vivo staining analysis islets mice confirmed that at a given moment,...
Although many regulatory networks involved in defining definitive endoderm have been identified, the mechanisms through which these interact to pattern are less well understood. To explore midgut patterning, we dissected transcriptional elements of nephrocan (Nepn), earliest known specific gene mice. We observed that Nepn expression is dramatically reduced Sox17−/− and Raldh2−/− embryos compared with wild-type embryos. further show directly regulated by Sox17 retinoic acid (RA) receptor via...
ABSTRACT Genome-wide association studies have identified hundreds of signals for type 2 diabetes (T2D), most which confer risk through effects on gene expression. We previously the transcription factor ZMIZ1 as a probable effector transcript in human islets, but how altered expression impacts T2D is unknown. now show that islets from carriers T2D-risk alleles reduced islet insulin content and glucose-stimulated secretion. To elucidate mechanism islet-cell dysfunction, we generated...
<p dir="ltr"><a href="" target="_blank">iPSC-derived human β-like cells (BLC) hold promise for both therapy and disease modelling, but their generation remains challenging functional analyses beyond transcriptomic morphological assessments remain limited. Here, we validate an approach using multicellular single cell electrophysiological tools to evaluate function of BLCs from pioneer protocols that can be easily adapted more differentiated BLCs. The Multi-Electrode Arrays (MEAs)...
<p dir="ltr"><a href="" target="_blank">iPSC-derived human β-like cells (BLC) hold promise for both therapy and disease modelling, but their generation remains challenging functional analyses beyond transcriptomic morphological assessments remain limited. Here, we validate an approach using multicellular single cell electrophysiological tools to evaluate function of BLCs from pioneer protocols that can be easily adapted more differentiated BLCs. The Multi-Electrode Arrays (MEAs)...
Abstract There are multiple independent genetic signals at the Ras-responsive element binding protein 1 ( RREB1 ) locus associated with type 2 diabetes risk, fasting glucose, ectopic fat, height, and bone mineral density. We have previously shown that loss of in pancreatic beta cells reduces insulin content impairs islet cell development function. However, is a widely expressed transcription factor metabolic impact vivo remains unknown. Here, we show male female global heterozygous knockout...
Abstract A rare loss-of-function variant p.Arg138* in SLC30A8 encoding the zinc transporter 8 (ZnT8) enriched Western Finland protects against type 2 diabetes (T2D). We recruited relatives of identified carriers and showed that protection was associated with better insulin secretion due to enhanced glucose responsiveness proinsulin conversion, especially compared individuals matched for genotype a common T2D risk , p.Arg325. In genome-edited human IPS-derived β-like cells, we establish...
Abstract iPSC-derived human β-like cells (BLC) hold promise for both therapy and disease modelling, but their generation remains challenging functional analyses beyond transcriptomic morphological assessments remain limited. Here, we validate an approach using multicellular single cell electrophysiological tools to evaluate BLCs functions. The Multi-Electrode Arrays (MEAs) measuring the extracellular electrical activity revealed that are electrically coupled, produce slow potential (SP)...
Summary Human embryonic stem cells (hESCs) are a potential unlimited source of insulin-producing β-cells for diabetes treatment. A greater understanding how form during development will improve current hESC differentiation protocols. As formed from NEUROG3-expressing endocrine progenitors, this study focused on characterizing the single-cell transcriptomes mouse and hESC-derived progenitors. To do this, 7,223 E15.5 6,852 E18.5 single were isolated Neurog3-Cre; Rosa26 mT/ mG embryos, allowing...