A5043570709- Atherosclerosis and Cardiovascular Diseases
- Single-cell and spatial transcriptomics
- RNA regulation and disease
- Cancer-related molecular mechanisms research
- Angiogenesis and VEGF in Cancer
- Congenital heart defects research
- Epigenetics and DNA Methylation
- Immune cells in cancer
- Cell Adhesion Molecules Research
- Genetic Associations and Epidemiology
- Bioinformatics and Genomic Networks
- Biomarkers in Disease Mechanisms
- Protease and Inhibitor Mechanisms
- Ferroptosis and cancer prognosis
- GDF15 and Related Biomarkers
- Adipose Tissue and Metabolism
- Circular RNAs in diseases
- Birth, Development, and Health
- RNA Research and Splicing
- Lipid metabolism and disorders
- Gene Regulatory Network Analysis
- Health, Environment, Cognitive Aging
- Computational Drug Discovery Methods
- Fatty Acid Research and Health
- Cardiovascular Disease and Adiposity
University of Cambridge
2019-2024
Palo Alto University
2024
Stanford University
2023-2024
Papworth Hospital
2023
Abstract Aims Quiescent, differentiated adult vascular smooth muscle cells (VSMCs) can be induced to proliferate and switch phenotype. Such plasticity underlies blood vessel homeostasis contributes disease development. Oligoclonal VSMC contribution is a hallmark of end-stage disease. Here, we aim understand cellular mechanisms underpinning generation this oligoclonality. Methods results We investigate the dynamics clone formation using confocal microscopy single-cell transcriptomics in...
Vascular inflammation underlies cardiovascular disease. smooth muscle cells (VSMCs) upregulate selective genes, including MMPs (matrix metalloproteinases) and proinflammatory cytokines upon local inflammation, which directly contribute to vascular disease adverse clinical outcome. Identification of factors controlling VSMC responses is therefore considerable therapeutic importance. Here, we determine the role Histone H3 lysine 9 di-methylation (H3K9me2), a repressive epigenetic mark that...
Vascular beds show different propensities for vascular pathologies, yet mechanisms explaining these fundamental differences remain unknown. We sought to build a transcriptomic, cellular, and spatial atlas of human arterial cells across multiple segments understand this phenomenon. found significant cell type-specific segmental heterogeneity. Determinants identity are predominantly encoded in fibroblasts smooth muscle cells, their differentially expressed genes particularly enriched...
Aberrant vascular smooth muscle cell (VSMC) homeostasis and proliferation characterize diseases causing heart attack stroke. Here we elucidate molecular determinants governing VSMC by reconstructing gene regulatory networks from single-cell transcriptomics epigenetic profiling. We detect widespread activation of enhancers at disease-relevant loci in proliferation-predisposed VSMCs. compared network rewiring between injury-responsive nonresponsive VSMCs, which suggested shared transcription...
Abstract Aims Vascular smooth muscle cells (VSMCs) accumulate in atherosclerotic plaques and exhibit remarkable phenotypic plasticity, contributing to both plaque growth stability. The plaque-stabilising fibrous cap is rich VSMC-derived cells, yet the cellular transitions regulatory mechanisms governing formation remain unclear. We aimed delineate VSMC associated with this critical process. Methods Results Mapping of lineage-traced VSMCs during development revealed investment prior...
Environmental exposure to dioxin has been linked increased myocardial infarction. Smooth muscle cells (SMC) in the coronary vasculature play a critical role atherosclerotic plaque remodeling due their phenotypic plasticity, however, detailed mechanism linking adverse SMC modulation is not well understood.
Abstract Mapping the genomic architecture of complex disease has been predicated on understanding that genetic variants influence risk through modifying gene expression. However, recent discoveries have revealed a significant burden heritability in common autoinflammatory disorders and coronary artery is mediated variation post-transcriptional modification RNA adenosine-to-inosine (A-to-I) editing. This catalyzed by ADAR enzymes, where ADAR1 edits specific immunogenic double stranded (dsRNA)...
Our lab has recently shown that several coronary artery disease (CAD)-protective genes inhibit the transition of smooth muscle cells from plaque-stabilising fibromyocytes (FMCs) to chondrocyte-like chondromyocytes (CMCs) localise areas associated with plaque vulnerability, namely acellular and calcified regions. To further investigate molecular mechanisms underlying FMCs CMCs, determine CMC impact on lesional stability, we induced SMC-specific deletion endochondral master regulator Sox9...
Adenosine-to-inosine (A-to-I) RNA editing is a common modification catalyzed by ADAR enzymes. ADAR1 serves crucial function to edit specific immunogenic double stranded (dsRNA) prevent the dsRNA sensor, MDA5 ( IFIH1 ), activating an interferon stimulated gene (ISG) response. Discoveries in human genetics now implicate deficient as causal mechanism for coronary artery disease (CAD) risk. Here, we show that atherosclerotic smooth muscle cells (SMCs) express at markedly higher levels compared...
The vascular adventitia has long been postulated to play a key role in atherosclerosis, but the relevant adventitial cell populations and mechanisms by which they influence atherosclerosis have remained elusive. To characterize cells their regulators, we combined single multi-omic murine human data with genetics. Single transcriptomic epigenetic analysis of both arterial tissue revealed unique population fibroblasts (AdvFib). Transcriptome epigenome disproportionate enrichment for coronary...
The fibrous cap of atherosclerotic plaques is essential for the plaque stability. Rupture leads to heart attacks and strokes, causes tens millions deaths globally every year. Identifying understanding cellular origins plasticity critical developing therapeutic strategies stabilize plaques. Utilizing lineage tracing mouse model, we demonstrated that cells arise from a predefined population expresses Notch3 at baseline. After pulse-labeling CreERT2 ; ROSA lsltdTomato Apoe -/- mice with...
Despite decades of progress, coronary artery disease (CAD) remains the top cause death worldwide. Additionally, trends in outcomes have worsened recently, highlighting critical need for additional treatments. Human genetics has identified over 300 loci associated with CAD, but understanding molecular mechanisms leading to a huge barrier developing new therapies. These CAD-associated are enriched smooth muscle cells (SMC) vascular wall, no current therapies target these cells. Since insulin...
We have recently identified rs2019090 and PDGFD as the functional variant gene mediating CAD risk at 11q22.3 locus, with our initial analysis using a global knockout (KO) model showing that this may promote phenotypic changes in smooth muscle cells (SMCs) plaque contribute to neointimal vascular calcification. Nonetheless, specific cell-type states through which confer disease remains unexplored.To delineate impact of SMC-derived signalling on cell state transitions progression...
Mapping the genomic architecture of complex disease has been predicated on understanding that genetic variants influence risk through modifying gene expression. However, recent discoveries have revealed a significant burden heritability in common autoinflammatory disorders and coronary artery is mediated variation post-transcriptional modification RNA adenosine-to-inosine (A-to-I) editing. This catalyzed by ADAR enzymes, where ADAR1 edits specific immunogenic double stranded (dsRNA) to...
The majority of variants identified by genome-wide association studies (GWAS) that influence coronary artery disease (CAD) risk reside in noncoding regions the genome, making it challenging to link them with genes they regulate. 9p21.3 locus is most impactful genetic for CAD. Due complexity this locus, causal and molecular mechanisms are poorly understood. Enhancers cell type specific, vascular smooth muscle cells (SMC) known have highest heritable CAD play a major role atherosclerotic...
ABSTRACT Rationale Vascular smooth muscle cell (VSMC) dysregulation is a hallmark of vascular disease, including atherosclerosis. In particular, the majority cells within atherosclerotic lesions are generated from pre-existing VSMCs and clonal nature has been documented for VSMC-derived in multiple disease models. However, mechanisms underlying generation oligoclonal phenotype proliferating unknown. Objective To understand cellular VSMC expansion disease. Methods Results Here we analyse...
Abstract Aberrant vascular smooth muscle cell (VSMC) homeostasis and proliferation are hallmarks of diseases causing heart attack stroke. To elucidate molecular determinants governing VSMC proliferation, we reconstructed gene regulatory networks from single transcriptomics epigenetic profiling. We find progressive activation enhancers at disease-relevant loci in VSMCs that don’t respond to injury proliferation-predisposed cells. Our analysis suggests while many transcription factors shared,...
<h3>Aims</h3> In atherosclerosis, vascular smooth muscle cells (VSMCs) dedifferentiate and acquire diverse phenotypes. These transdifferentiation pathways are poorly understood, including that underpinning generation of the VSMC-rich, plaque-stabilising fibrous cap. We aim to delineate VSMC in disease, with focus on cap formation. <h3>Methods Results</h3> Using single-cell RNA-sequencing VSMCs we computationally inferred five a common intermediate state (SCA1/Ly6a+, Vcam1+) but distinct...
Adenosine-to-inosine (A-to-I) RNA editing is a common modification catalyzed by ADAR (adenosine deaminase acting on RNA) enzymes. ADAR1 serves crucial function to edit specific immunogenic double stranded (dsRNA) molecules prevent the dsRNA sensor, MDA5 ( IFIH1 ), activating an interferon stimulated gene (ISG) response. Discoveries in human genetics now implicate deficient as causal mechanism coronary artery disease (CAD). Here, we reveal atherosclerosis, smooth muscle cells (SMCs) express...
Abstract Rationale Vascular beds have distinct susceptibility to atherosclerosis and aneurysm, yet the biological underpinnings of vascular bed specific disease risk are largely unknown. tissues different developmental origins which may influence global chromatin accessibility. Understanding accessibility gene expression profiles on single cell resolution is crucial gain insight into risk. Objective We aim understand, at resolution, across in healthy adult mouse provide potential mechanisms...
<h3></h3> In healthy blood vessels, vascular smooth muscle cells (VSMCs) exist in a contractile, quiescent state but can switch phenotype to activate proliferation, migration and remodelling of the extracellular matrix. Phenotypically switched VSMCs contribute most within neointimal lesions, characteristic atherosclerosis in-stent restenosis, diseases that underlie heart attack stroke. Using multicolour 'Confetti' VSMC-specific lineage tracing animal models disease, we showed extensive VSMC...