Document text
Principal Investigator: SHU CHIEN
Organization: UNIVERSITY OF CALIFORNIA, SAN DIEGO
Fiscal Year: 2024
Award: $840,873
Funding agency: National Heart Lung and Blood Institute
Project Summary
Shear stresses resulting from distinct blood flow patterns impact endothelial cell (EC) functions.
ECs under atheroprone flow exhibit increased proliferation, inflammation, and glycolysis,
compared to those under atheroprotective flow. Our recent studies have uncovered a novel role
of epitranscriptional regulation (i.e., functional changes to RNAs without altered nucleotide
sequence) in EC mechanobiology. Thus, atheroprone flow induces METTL3, a methyltransferase
that catalyzes N6-methyladenosine (m6A) to result in the most abundant RNA modification found
in eukaryotes. Our newly conducted preliminary studies indicate that METTL3 inhibition in ECs
suppresses the atheroprone flow-induced pro-inflammatory response and glycolysis. Through
transcriptome and epitranscriptome mapping, we found that METTL3 caused hypermethylation
of the mRNAs encoding the key enzymes involved in glycolysis and pentose phosphate pathway
(PPP, a branch of glycolysis). These findings led to the guiding hypothesis that atheroprone flow
upregulates METTL3 to modulate m6A epitranscriptomes and hence promote glycolysis and PPP
in ECs, thus contributing to EC dysfunction and atherosclerosis. The four specific aims proposed
to test this hypothesis are: Aim 1. To delineate the dynamics of METTL3-regulated
epitranscriptomes in ECs under atheroprone vs. atheroprotective flow patterns; Aim 2. To identify
the METTL3-modulated m6A RNA targets that drive the atheroprone flow enhancement of EC
glycolysis and PPP; Aim 3. To elucidate the effects of the flow-regulated EC m6A
epitranscriptomes on the phenotypic changes of co-cultured SMCs and EC glycolysis by SRS
imaging; Aim 4. To validate flow regulation of METTL3 and m6A epitranscriptomes in mouse
atherosclerosis models. This interdisciplinary research will unveil novel epitranscriptional
mechanisms underlying EC mechanobiology and atherosclerotic diseases.
Terms: <6-Phosphofructo-2-kinase><6PF2K><ATP-D-Fructose-6-phosphate 2-phosphotransferase><Adhesions><Arterial Fatty Streak><Arterial Fatty Streaks><Atheroma><Atheromatous><Atheromatous degeneration><Atheromatous plaque><Atherosclerosis><Atherosclerotic Cardiovascular Disease><Base Sequence><Binding Proteins><Biology><Blood Vessels><Blood flow><Blood monocyte><Cardiovascular Diseases><Carotid Arteries><Causality><Cell Function><Cell Physiology><Cell Process><Cellular Function><Cellular Physiology><Cellular Process><Closure by Ligation><Co-culture><Cocultivation><Coculture><Coculture Techniques><D-Glucose><DNA><Data><Deoxyribonucleic Acid><Dextrose><Disease><Disorder><Dysfunction><EC 2.1.1><Endothelial Cells><Endothelium><Enzyme Gene><Enzymes><Etiology><Eukaryota><Eukaryote><Exhibits><Family><Fructose><Functional disorder><Gene Expression><Genes><Glucose><Glycolysis><Glycolysis Inhibition><Health><Hexose Monophosphate Shunt><Human><Hypermethylation><Image><In Vitro><Inflammasome><Inflammation><Inflammatory><Inflammatory Response><Interdisciplinary Research><Interdisciplinary Study><Knowledge><Label><Levulose><Ligand Binding Protein><Ligand Binding Protein Gene><Ligation><Link><MEFV gene product><Maps><Marrow monocyte><Mediating><Messenger RNA><Metabolic><Methyltransferase><Mice><Mice Mammals><Microscopy><Modeling><Modern Man><Modification><Multidisciplinary Collaboration><Multidisciplinary Research><Murine><Mus><Non-Polyadenylated RNA><Nucleotide Sequence><Pathologic Constriction><Pathological Constriction><Pattern><Pentose Phosphate Pathway><Pentose Phosphate Shunt><Pentose Shunt><Pentosephosphate Pathway><Pentosephosphate Shunt><Phenotype><Phosphofructokinase-2><Physiopathology><Proliferating><Protein Binding><R-Series Research Projects><R01 Mechanism><R01 Program><RNA><RNA Editing><RNA Gene Products><RNA, Messenger, Editing><Reader><Regulation><Research><Research Grants><Research Project Grants><Research Projects><Ribonucleic Acid><Role><Stenosis><Subcellular Process><System><Testing><Transaldolase><Trees><Vascular Diseases><Vascular Disorder><Visualization><atherogenesis><atheromatosis><atheroprotection><atheroprotective><atherosclerosis plaque><atherosclerotic disease><atherosclerotic lesions><atherosclerotic plaque><atherosclerotic vascular disease><blood vessel disorder><bound protein><cardiovascular disorder><causation><crosslink><disease causation><endothelial dysfunction><epitranscriptome><epitranscriptomics><gain of function><global gene expression><global transcription profile><glucokinase regulatory protein><glucose metabolism><hemodynamics><imaging><improved><in vivo><insight><knock-down><knockdown><mRNA><marenostrin><methylase><monocyte><mutant><novel><nucleic acid sequence><overexpress><overexpression><pathophysiology><pyrin><shear stress><social role><transcriptome><transcriptomics><translatome><transmethylase><vascular><vascular dysfunction><vasculopathy><vulnerable plaque>