Molecular Regulation of Atherosclerosis Regression - Renewal

NIH Pandemic-Era Grants

Pandemic Era Grants

2024

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Principal Investigator: Edward A Fisher
Organization: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
Fiscal Year: 2024
Award: $819,950
Funding agency: National Heart Lung and Blood Institute

ABSTRACT
Coronary plaques begin their progression in childhood, making their reversal an important clinical goal in
adulthood. The understanding of mechanisms underlying atherosclerosis regression has been understudied
compared to plaque progression. Atherosclerosis represents a failure to resolve the maladaptive immune
response that maintains plaque growth through the accumulation of pro-inflammatory immune cells.
 The central inflammatory cell in the plaque is the macrophage (Mø) in the activated state. We previously
showed that plaque regression in mouse models is characterized by the enrichment of Møs in the inflammation
resolving state (which we will refer to as proR-Møs). We have recently shown that these proR-Møs are required
for regression. We also have observed in regressing plaques increased numbers of inflammation dampening
CD4+ regulatory T cells (Tregs), which prevent the expansion of effector T cells and support proR-Mø functions.
Furthermore, our results point to Wnt-signaling and chemokine receptor CCR7 as key pathways associated with
a pro-resolving environment. We hypothesize that all of these factors play important roles in the reprogramming
of the plaque inflammatory milieu to enable inflammation tissue repair in the artery wall and thereby promote
atherosclerosis regression.
 The development of novel therapies for atherosclerosis must also take into account “real world” clinical
issues. Accumulating data now show that the majority of treated patients intermittently adhere to statins, which
increases their CAD risk. We hypothesize that epigenetic reprogramming of macrophages and their precursors
by IH through trained immunity mediates these adverse effects on atherosclerosis, further hindering inflammation
resolution and rendering plaques susceptible to accelerated disease and refractory to regression. We have
developed the following specific aims to investigate the factors and pathways that drive or hinder
inflammation resolution and plaque remodeling during atherosclerosis regression:
Aim 1: To study the regulation of the inflammation-resolving properties of plaque Møs by Wnt-signaling.
Aim 2: To determine the role of CCR7 in the resolution of atherosclerotic inflammation and plaque
regression.
Aim 3: To establish the mechanistic basis for increased coronary artery disease risk in patients with
intermittent statin adherence.
In summary, this proposal represents an exciting opportunity to continue to combine our collective expertises to
address crucial gaps in our knowledge of the resolution of inflammation in atherosclerosis.

Terms: <21+ years old><Acceleration><Address><Adherence><Adult><Adult Human><Adverse effects><Antigen Presentation><Arteries><Atherosclerosis><Atherosclerotic Cardiovascular Disease><Autoregulation><B-Cell Stimulatory Factor 1 Gene><BSF-1 Gene><BSF1 Gene><Body Tissues><Cardiac infarction><Cause of Death><Cell Body><Cells><Chemokine Receptor Gene><Childhood><Cholesterol><Clinical><Coronary Arteriosclerosis><Coronary Artery Disease><Coronary Artery Disorder><Coronary Atherosclerosis><Country><Data><Development><Disease><Disorder><Emigrations><Environment><Epigenetic><Epigenetic Change><Epigenetic Mechanism><Epigenetic Process><Event><Exposure to><Failure><Generalized Growth><Goals><Groups at risk><Growth><Homeostasis><Hypercholesteremia><IL-4 Gene><IL4><IL4 gene><Immune><Immune memory><Immune response><Immunes><Immunity><Immunologic Memory><Immunological Memory><Immunological response><Impairment><In Vitro><Inflammation><Inflammatory><Interleukin-4 Gene><Interleukin-4 Precursor Gene><Knowledge><Lipids><Lymph Node Reticuloendothelial System><Lymph node proper><Lymphatic nodes><Macrophage><Mediating><Molecular><Movement><Myocardial Infarct><Myocardial Infarction><Mφ><Pathway interactions><Patients><People at risk><Persons at risk><Physiological Homeostasis><Play><Population><Populations at Risk><Predisposition><Property><Refractory><Regulation><Regulatory T-Lymphocyte><Resolution><Risk><Risk Factors><Role><Sterols><Susceptibility><Systems Biology><T-Cells><T-Lymphocyte><Teff cell><Tissue Growth><Tissues><Training><Treg><WNT Signaling Pathway><WNT signaling><adulthood><anamnestic reaction><atheromatosis><atherosclerotic coronary disease><atherosclerotic disease><atherosclerotic vascular disease><body movement><cardiac infarct><cell type><chemokine receptor><coronary arterial disease><coronary attack><coronary infarct><coronary infarction><coronary plaque><cytokine><developmental><disease risk><disorder risk><effector T cell><epigenetically><heart attack><heart infarct><heart infarction><high blood cholesterol><host response><hypercholesterolemia><immune system response><immunoresponse><in vitro Model><in vivo><inflammatory environment><inflammatory milieu><lipid mediator><lymph gland><lymph nodes><lymphnodes><mouse model><murine model><new drug treatments><new drugs><new pharmacological therapeutic><new therapeutics><new therapy><next generation therapeutics><novel><novel drug treatments><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel therapeutics><novel therapy><ontogeny><pathway><pediatric><peripheral tolerance><prevent><preventing><regulatory T-cells><resolutions><response><restoration><scRNA-seq><secondary immune response><single cell RNA-seq><single cell RNAseq><single cell expression profiling><single cell transcriptomic profiling><single-cell RNA sequencing><social role><thymus derived lymphocyte><tissue repair><transcriptome profiling><transcriptomic profiling>