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Principal Investigator: Annarita Di Lorenzo
Organization: WEILL MEDICAL COLL OF CORNELL UNIV
Fiscal Year: 2024
Award: $575,444
Funding agency: National Heart Lung and Blood Institute
Inflammatory macrophages play a key role in the development and progression of the atherosclerosis,
leading to myocardial infarction (MI). Sphingolipids are both membrane components and signaling
molecules. Ceramide and Sphingosine-1-phosphate (S1P), bioactive and interchangeable
sphingolipids, regulate a variety of cellular processes, including cell growth and survival, apoptosis, and
immune and cardiovascular functions. As cholesterol, altered sphingolipid metabolism has been
implicated in atherosclerosis. Whereas extensive studies on molecular regulation of cholesterol
biosynthesis led to the discovery of statins, widely used lowering-cholesterol drugs, how sphingolipid
biosynthesis is regulated and its pathophysiological implication are poorly understood.
In this regard, our lab discovered a novel mechanism by which sphingolipid biosynthesis is regulated in
mammals. Nogo-B, a membrane protein of the ER, binds to and inhibits serine palmitoyltransferase
(SPT), the rate-limiting enzyme of the sphingolipid de novo biosynthesis[11]. Mice lacking Nogo-B are
protected from inflammation, hypertension and heart failure, in part via endothelial S1P signaling.
Our long-term goal is to understand how sphingolipid metabolism and signaling is regulated and its
impact on coronary atherosclerosis development and progression.
Recently, we developed a novel mouse model able to develop of coronary lesions, that progress to
disruption (rupture, erosion) or occlusion leading to MI. Our hypothesis that Nogo-B downregulates SL
metabolism and signaling, mainly ceramide and S1P, to control macrophage functions in coronary
inflammation, atherosclerosis development and progression to MI. The rational is that the discovery of
new mechanisms regulating the development and progression of atherosclerosis will provide potential
therapeutic targets for coronary artery disease. Thus, we propose to: 1) investigate the role of MΦ
Nogo-B in the susceptibility of mice to coronary atherosclerosis development and progression to MI; 2)
Decipher the impact of Nogo-B-regulated ceramide and S1P signaling on MΦ biology and mechanistic
insights. This contribution is significant since will identify novel targets for the treatment of coronary
artery disease, especially since available therapies have been only partially successful, and beyond the
statins, there are currently no effective pharmacological strategies that effectively address vascular
inflammation. The proposed research is innovative because we investigate a relevant but understudied
metabolic pathway by using a novel mouse model of coronary atherosclerosis with progression to MI
that better recapitulates the human disease, a heretofore-unexamined process.
Terms: <(TNF)-α><AcLDL><Address><Anabolism><Apo-E><ApoE><ApoE protein><Apolipoprotein E><Apoptosis><Apoptosis Pathway><Arterial Fatty Streak><Arterial Fatty Streaks><Atheroma><Atheromatous><Atheromatous degeneration><Atheromatous plaque><Atherosclerosis><Atherosclerotic Cardiovascular Disease><Binding><Biological Function><Biological Process><Biology><Blood Plasma><Cachectin><Cardiac infarction><Cardiovascular><Cardiovascular Body System><Cardiovascular Organ System><Cardiovascular Physiology><Cardiovascular system><Carotid Arteries><Cause of Death><Cell Body><Cell Communication and Signaling><Cell Function><Cell Physiology><Cell Process><Cell Signaling><Cell Survival><Cell Viability><Cells><Cellular Expansion><Cellular Function><Cellular Growth><Cellular Immune Function><Cellular Physiology><Cellular Process><Ceramides><Cholesterol><Cholesterol Esters><Cholesteryl Esters><Clinical><Complex><Coronary><Coronary Arteriosclerosis><Coronary Artery Disease><Coronary Artery Disorder><Coronary Atherosclerosis><Data><Development><Disease><Disease Progression><Disorder><Down-Regulation><Drugs><Economic Burden><Endoplasmic Reticulum><Endothelium><Enzyme Gene><Enzymes><Ergastoplasm><Event><Foam Cells><G Protein-Complex Receptor><G Protein-Coupled Receptor Genes><G-Protein-Coupled Receptors><GPCR><Gene Transcription><Genetic><Genetic Transcription><Goals><Grant><Health><Heart Vascular><Heart failure><Heterogeneity><Human><Hypertension><Immune><Immunes><Inflammation><Inflammatory><Intermediary Metabolism><Intracellular Communication and Signaling><Lesion><Lipids><Macrophage><Macrophage-Derived TNF><Mammalia><Mammals><Mediator><Medication><Membrane><Membrane Protein Gene><Membrane Proteins><Membrane-Associated Proteins><Metabolic Pathway><Metabolic Processes><Metabolism><Mice><Mice Mammals><Modeling><Modern Man><Molecular><Molecular Interaction><Monocyte-Derived TNF><Mortality Determinants><Murine><Mus><Myocardial Infarct><Myocardial Infarction><Mφ><Names><Operative Procedures><Operative Surgical Procedures><OxLDL><PP2A><PP2A Subunit B Prime><Pathway interactions><Pharmaceutical Preparations><Phenotype><Phosphoprotein Phosphatase><Phosphoprotein Phosphatase-2C><Phosphoprotein Phosphohydrolase><Phosphorylation><Phosphotyrosyl Phosphatase Activator><Plasma><Plasma Serum><Play><Population><Predisposition><Process><Programmed Cell Death><Protein Phosphatase 2A Regulatory Subunit B Prime><Protein Phosphatase 2A Regulatory Subunit PR53><Protein Phosphatase C><Protein Phosphatase Gene><Protein Phosphatase-1><Protein Phosphatase-2A><Protein Phosphorylation><Protein phosphatase><Public Health><RNA Expression><Regulation><Reporting><Research><Reticuloendothelial System, Serum, Plasma><Role><Rupture><Signal Transduction><Signal Transduction Systems><Signaling><Signaling Molecule><Sphingolipids><Subcellular Process><Surface Proteins><Surgical><Surgical Interventions><Surgical Procedure><Susceptibility><TNF><TNF A><TNF Alpha><TNF gene><TNF-α><TNFA><TNFα><Testing><Therapeutic><Transcription><Tumor Necrosis Factor><Tumor Necrosis Factor-alpha><Up-Regulation><Upregulation><Vascular Hypertensive Disease><Vascular Hypertensive Disorder><acetyl-LDL><acetyl-low density lipoproteins><acetylated LDL><acetylated low density lipoprotein><aortic valve><atheromatosis><atherosclerosis plaque><atherosclerotic coronary disease><atherosclerotic disease><atherosclerotic lesions><atherosclerotic plaque><atherosclerotic vascular disease><biological signal transduction><biosynthesis><cardiac failure><cardiac infarct><cardiovascular function><cell growth><cholesterol biosynthesis><circulatory system><coronary arterial disease><coronary attack><coronary infarct><coronary infarction><coronary lesion><developmental><drug discovery><drug/agent><genetic approach><genetic strategy><heart attack><heart infarct><heart infarction><high blood pressure><human disease><hyperpiesia><hyperpiesis><hypertensive disease><hypertensive disorder><immune function><innovate><innovation><innovative><insight><membrane structure><metabolism measurement><metabolomics><metabonomics><mouse model><murine model><name><named><naming><novel><ox-LDL><oxidized LDL><oxidized low density lipoprotein><pathway><pharmacologic><scRNA-seq><serine C-palmitoyltransferase><serine palmitoyltransferase><single cell RNA-seq><single cell RNAseq><single cell expression profiling><single cell transcriptomic profiling><single-cell RNA sequencing><social role><sphingosine 1-phosphate><surgery><therapeutic agent development><therapeutic development><therapeutic target><vascular inflammation><vulnerable plaque>