A5083615835- Cardiac Fibrosis and Remodeling
- Single-cell and spatial transcriptomics
- Congenital heart defects research
- Bioinformatics and Genomic Networks
- Tissue Engineering and Regenerative Medicine
- Protein Structure and Dynamics
- Cell Adhesion Molecules Research
- Congenital Heart Disease Studies
- Cardiac Structural Anomalies and Repair
- Advanced Proteomics Techniques and Applications
- Computational Drug Discovery Methods
- Angiogenesis and VEGF in Cancer
- RNA Research and Splicing
- Cell death mechanisms and regulation
- Genomics and Chromatin Dynamics
- Machine Learning in Bioinformatics
- SARS-CoV-2 and COVID-19 Research
- Cardiovascular and Diving-Related Complications
- Immune cells in cancer
- Acute Ischemic Stroke Management
- RNA and protein synthesis mechanisms
- Extracellular vesicles in disease
- Cancer-related molecular mechanisms research
- Renal and related cancers
- Neutrophil, Myeloperoxidase and Oxidative Mechanisms
James A. Haley Veterans' Hospital
2025
University of South Florida
2025
UNSW Sydney
2019-2024
The University of Queensland
2012-2024
Victor Chang Cardiac Research Institute
2017-2024
St Vincent's Clinic
2019-2023
Stem Cells Australia
2017-2019
The University of Melbourne
2017-2019
Australian Research Council
2018
Westmead Hospital
2017
Besides cardiomyocytes (CM), the heart contains numerous interstitial cell types which play key roles in repair, regeneration and disease, including fibroblast, vascular immune cells. However, a comprehensive understanding of this interactive community is lacking. We performed single-cell RNA-sequencing total non-CM fraction enriched (Pdgfra-GFP+) fibroblast lineage cells from murine hearts at days 3 7 post-sham or myocardial infarction (MI) surgery. Clustering >30,000 single identified >30...
Abstract Endothelial cells play a critical role in the adaptation of tissues to injury. Tissue ischemia induced by infarction leads profound changes endothelial cell functions and can induce transition mesenchymal state. Here we explore kinetics individual cellular responses after myocardial using single RNA sequencing. This study demonstrates time dependent switch proliferation inflammation associated with transient metabolic gene signatures. Trajectory analysis reveals that majority 3 7...
ABSTRACT Recent advances in the generation of kidney organoids and culture primary nephron progenitors from mouse human have been based on knowledge molecular basis development mice. Although gene expression during has intensely investigated, single cell profiling provides new opportunities to further subsect component types signalling networks at play. Here, we describe analysis 6732 transcriptomes fetal [embryonic day (E)18.5] 7853 sorted progenitor cells (E14.5). These datasets provide...
Aging is a major risk factor for cardiovascular disease. Although the impact of aging has been extensively studied, little known regarding processes in cells heart. Here we analyzed transcriptomes hearts 12-week-old and 18-month-old mice by single-nucleus RNA-sequencing. Among all cell types, aged fibroblasts showed most significant differential gene expression, increased RNA dynamics, network entropy. Aged exhibited significantly changed expression patterns inflammatory, extracellular...
High-throughput single-cell RNA-seq (scRNA-seq) is a powerful tool for studying gene expression in single cells. Most current scRNA-seq bioinformatics tools focus on analysing overall levels, largely ignoring alternative mRNA isoform expression. We present computational pipeline, Sierra, that readily detects differential transcript usage from data generated by commonly used polyA-captured technology. validate Sierra comparing cardiac cell types to bulk of matched populations, finding...
Macrophages are key cellular contributors to the pathogenesis of COVID-19, disease caused by virus SARS-CoV-2. The SARS-CoV-2 entry receptor ACE2 is present only on a subset macrophages at sites infection in humans. Here, we investigated whether can enter macrophages, replicate, and release new viral progeny; need sense replicating drive cytokine release; and, if so, involved these mechanisms. We found that could enter, but did not replicate within, ACE2-deficient human primary induce...
A mechanistic connection between aging and development is largely unexplored. Through profiling age-related chromatin transcriptional changes across 22 murine cell types, analyzed alongside previous mouse human organismal maturation datasets, we uncovered a transcription factor binding site (TFBS) signature common to both processes. Early-life candidate cis-regulatory elements (cCREs), progressively losing accessibility during aging, are enriched for cell-type identity TFBSs. Conversely,...
Single-cell technology has allowed researchers to probe tissue complexity and dynamics at unprecedented depth in health disease. However, the generation of high-dimensionality single-cell atlases virtual three-dimensional tissues requires integrated reference maps that harmonize disparate experimental designs, analytical pipelines, taxonomies. Here, we present a comprehensive transcriptome integration map cardiac fibrosis, which underpins pathophysiology most cardiovascular diseases. Our...
Abstract Motivation: The determinants of kinase-substrate phosphorylation can be found both in the substrate sequence and surrounding cellular context. Cell cycle progression, interactions with mediating proteins even prior events are necessary for kinases to maintain specificity. While much work has focussed on use sequence-based methods predict sites, there been very little invested into application systems biology understand phosphorylation. Lack specificity many kinase binding motifs...
Signaling pathways are the key biological mechanisms that transduce extracellular signals to affect transcription factor mediated gene regulation within cells. A number of computational methods have been developed identify topological structure a specific signaling pathway using protein-protein interaction data, but they not designed for identifying active in an unbiased manner. On other hand, there statistical based on sets or data can prioritize likely pathways, do make full use link...
Novel regenerative therapies may stem from deeper understanding of the mechanisms governing cardiovascular lineage diversification. Using enhancer mapping and live imaging in avian embryos, genetic tracing mice, we investigated spatio-temporal dynamics progenitor populations. We show that expression cardiac transcription factor Nkx2.5 marks a mesodermal population outside crescent extraembryonic lateral plate mesoderm, with characteristics hemogenic angioblasts. Extra-cardiac progenitors...
Reversal of ischemia is mediated by neo-angiogenesis requiring endothelial cell (EC) and pericyte interactions to form stable microvascular networks. We describe an unrecognized role for tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) in potentiating vessel stabilization. show that the endothelium a major source TRAIL healthy circulation compromised peripheral artery disease (PAD). EC deletion vivo or vitro inhibited neo-angiogenesis, recruitment, stabilization, resulting...
Protein synthesis is finely regulated across all organisms, from bacteria to humans, and its integrity underpins many important processes. Emerging evidence suggests that the dynamic range of protein abundance greater than observed at transcript level. Technological breakthroughs now mean sequencing-based measurement mRNA levels routine, but protocols for measuring remain both complex expensive. This paper introduces a Bayesian network integrates transcriptomic proteomic data predict model...
Irreversible fibrosis is a hallmark of myocardial infarction (MI) and heart failure. Extracellular matrix protein-1 (ECM-1) up-regulated in these hearts, localized to fibrotic, inflammatory, perivascular areas. ECM-1 originates predominantly from fibroblasts, macrophages, pericytes/vascular cells uninjured human mouse M1 M2 macrophages myofibroblasts after MI. stimulates fibroblast-to-myofibroblast transition, up-regulates key fibrotic inflammatory pathways, inhibits cardiac fibroblast...
Abstract Despite the high prevalence of heart failure in western world, there are few effective treatments. Fibulin-3 is a protein involved extracellular matrix (ECM) structural integrity, however its role unknown. We have demonstrated, using single cell RNA-seq, that fibulin-3 was highly expressed quiescent murine cardiac fibroblasts, with expression highest prior to injury and late post-infarct (from ~ day-28 week-8). In humans, upregulated left ventricular tissue plasma patients. knockout...
SUMMARY The interstitial and perivascular spaces of the mammalian heart contain a highly interactive tissue community essential for cardiac homeostasis, repair regeneration. Mesenchymal cells (fibroblasts) are one most abundant cell types, playing key roles as sentinels, architects, paracrine signaling hubs lineage precursors, linked to disease through their in inflammation fibrosis. Platelet-derived growth factors (PDGFs) secreted by several types involved injury repair, recognized mitogens...
Abstract Motivation Genome-wide association studies are identifying single nucleotide variants (SNVs) linked to various diseases, however the functional effect caused by these is often unknown. One potential effect, loss or gain of protein phosphorylation sites, can be induced through variations in key amino acids that disrupt introduce valid kinase binding patterns. Current methods for predicting SNVs on operate sequence content reference and variant proteins. However, consideration acid...
Unlike single-gene mutations leading to Mendelian conditions, common human diseases are likely be emergent phenomena arising from multilayer, multiscale, and highly interconnected interactions. Atrial ventricular septal defects the most forms of cardiac congenital anomalies in humans. (ASD) show an open communication between left right atria postnatally, potentially resulting serious hemodynamic consequences if untreated. A milder form atrial defect, patent foramen ovale (PFO), exists about...
The half-life of a protein is regulated by range system properties, including the abundance components degradative machinery and modifiers. It also influenced protein-specific such as protein's structural make-up interaction partners. New experimental techniques coupled with powerful data integration methods now enable us to not only investigate what features govern stability in general, but build models that identify properties determine each metabolic stability.In this work we present five...