Vascular biology
Chronic metabolic diseases
Bioinformatics of multi-omics data
Research Areas
Protein neddylation in vascular integrity (Collaboration with Dr. Huabo Su at Augusta University)
Neddylation is a reversible post-translational modification that attaches one or more ubiquitin-like NEDD8 moieties to substrates via a NEDD8-specific E1-E2-E3 enzymatic cascade. Emerging evidence shows that neddylation plays significant roles in metabolic disorders, cardiomyopathies, immunity, and other pathophysiological events. However, its role in the endothelium and vascular diseases is unclear. The goal of this research is to establish the pathophysiological significance of neddylation in endothelium and to identify key downstream effectors in endothelial cells. We uncovered a link between neddylation perturbations and vascular diseases in humans and mouse models. We further showed that endothelia cell-specific inhibition of neddylation by deleting NEDD8 activating enzyme-1 (NAE1) in adult mice causes mortality from pronounced vasculopathy and multi-organ damage characterized by loss of EC integrity, cell death, inflammation, and hemorrhage. This research will provide a comprehensive mechanistic understanding of protein neddylation in safeguarding endothelial function and integrity. This is a key step toward our long-term goal to establish the clinical relevance of its findings and develop novel therapeutic strategies to precisely modulate protein neddylation for vascular diseases with minimized adverse effects.
New regulators of the vascular endothelium in atherosclerosis
Atherosclerosis is a chronic disease of the vessel wall characterized by low-grade inflammation and lipid accumulation. It is the most common cause of cardiovascular disease, which remains the leading cause of death in the United States. To reduce cardiovascular risk, LDL cholesterol-lowering therapies, such as statins, are widely used. However, maximally tolerated statin therapy may be inadequate to reduce the risk of atherosclerotic cardiovascular disease in a subgroup of patients, and long-term use of statins has been linked to side effects such as myopathy, hepatotoxicity, or peripheral neuropathy. As such, there is a critical need to develop new therapies directed at additional targets that can address the residual risk in a subset of patients after the existing therapies. The vascular endothelium is a single layer of cells that lines the blood vessels and plays a key role in the development of atherosclerosis. We aim to identify new regulators that control endothelium homeostasis and function employing a variety of state of the art approaches including single cell transcriptome analysis and proximity proteomics in combination with validation in human specimens. We also aim to establish the causal effects of findings from genome-wide association studies (GWAS). We hope to provide targets for therapies protecting endothelium function and treat atherosclerosis.
Nuclear receptor signaling, inflammation, and lipid metabolism in fatty liver disease
Metabolic dysfunction-associated steatotic liver disease (MASLD) affects about 30% of U.S. adults. It can progress from simple steatosis to metabolic dysfunction-associated steatohepatitis, cirrhosis, and carcinoma. To develop new therapies, we must improve our understanding of gene expression regulation and signaling transduction in MASLD. Our foundational work identified constitutive androstane receptor (CAR) that acts downstream of matrin-3 regulating lipid accumulation and stress response in the liver linking matrin-3 to the etiology of metabolic liver diseases. Our preliminary data demonstrated that high-fat diet feeding induces both matrin-3 and CAR expression, and they have a very strong positive correlation in human livers. In addition, we found that the expression of CAR discords with the expression of its target genes in the liver responding to nutritional and metabolic stress, and CAR is highly expressed in nuclei in the liver challenging the prevailing view of its mode of action. We will employ various state-of-the-art approaches, including multi-omics techniques (easyCLIP, lipidomics, single-nucleus Multiome), systems biology, new lines of conditional knockout mice, and mouse phenotyping to demonstrate the protective role of matrin-3-CAR axis in metabolic liver disease. We will reveal new knowledge of the etiology of metabolic liver disease and its associated cardiometabolic disease to inform new therapeutic strategies.
Bioinformatics and Data Analysis
We integrate cutting-edge bioinformatics tools to analyze next-generation sequencing data. Our expertise in data analysis enables us to extract meaningful insights from complex datasets, driving impactful discoveries in biomedical research. We can analyze the following data:
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Bulk RNA-sesq
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ATAC-seq
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ChIP-seq
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Single-cell RNA-seq
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We can perform reads quality control, mapping to reference genome, cell cluster annotation, differential expression, gene ontology and pathway analysis, and generate high-quality figures for publication.
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