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Principal Investigator: Hanrui Zhang
Organization: COLUMBIA UNIVERSITY HEALTH SCIENCES
Fiscal Year: 2024
Award: $632,206
Funding agency: National Heart Lung and Blood Institute
Lipid-lowering approaches reduce atherosclerotic cardiovascular disease (ACVD), but significant residual risk
remains. Macrophage (Mφ) accumulation and defective phagocytic clearance of apoptotic cells (ACs) by Mφs,
i.e., defective efferocytosis, promote atherosclerotic plaque vulnerability and subsequent acute cardiovascular
events. Enhancing efferocytosis represents a potential therapeutic strategy for residual risk reduction in ACVD.
Discovering novel genes that can be harnessed to enhance efferocytosis addresses a major knowledge gap and
provides opportunities for new ACVD therapeutics. As discovered in our genome-wide CRISPR screen of
efferocytosis regulators, Pdcd6ip deficiency enhances Mφ efferocytosis, representing a novel therapeutic
opportunity in atherosclerosis and management of CVD residual risk. Preliminary data show that transplantation
of Pdcd6ip-/- mice bone marrow into atherosclerosis-prone Ldlr-/- mice increases features of plaque stability. This
PPG project will test the central hypothesis that Pdcd6ip acts as a molecular break on Mφ efferocytosis and
can be harnessed to ameliorate athero-progression or to promote athero-regression through effects on plaque
stabilization, the central theme. Integrating with Drs. Tall and Tabas, the project will assess the therapeutic
impact of Pdcd6ip inhibition on atherosclerosis with clonal hematopoiesis (CH) mutations, with implications for
inflammation-related residual risk in CH patients. Aim 1 will determine how Pdcd6ip deficiency enhances
efferocytosis in vitro in murine and human Mφs. Our data show that Pdcd6ip-/- induces cytokinesis arrest and
increased formation of polyploid Mφ that demonstrate superior capability of continuing efferocytosis, suggesting
a “super-eater” phenotype. Mononuclear Mφs with Pdcd6ip-/- also show enhanced primary efferocytosis, though
not continuing efferocytosis. We will test the hypothesis that Pdcd6ip deficiency enhances efferocytosis via both
polyploidy-dependent and -independent mechanisms. Aim 2 will determine if harnessing Pdcd6ip inhibition
enhances efferocytosis to ameliorate athero-progression or to promote athero-regression in mice. We will
determine: (A) whether Pdcd6ip deficiency ameliorates progression via converting proliferating Mφs to “super-
eater” polyploid Mφs, including in JAK2-CH mice; and (B) whether Pdcd6ip deficiency promotes regression via
enhancing efferocytosis-resolution cycle, including in DNMT3A-CH mice. Using fate-mapping and scRNA-seq,
we will also address how Pdcd6ip deficiency promotes plaque stability via Mφ and stromal cell crosstalk (with
Drs. Tall, Tabas, Reilly, Cores B&C). Aim 3 integrates the histological, clinical, transcriptomic, and spatial
transcriptomics data of biobanked human plaques in the Munich Vascular Biobank (Dr. Maegdefessel, Core C)
to prioritize potential efferocytosis regulators identified in our genome-wide CRISPR screen that are associated
with human atheroma. The prioritized genes will accelerate mechanistic studies and support the translational
promise of enhancing efferocytosis for residual risk reduction in ACVD, particularly in CH patients. In summary,
our work will provide insights into new approaches to enhance Mφ efferocytosis and mitigate residual ACVD risk.
Terms: <Abbreviations><Abscission><Acceleration><Acute><Address><Affect><Apoptotic><Area><Arterial Fatty Streak><Arterial Fatty Streaks><Atheroma><Atheromatous><Atheromatous degeneration><Atheromatous plaque><Atherosclerosis><Atherosclerotic Cardiovascular Disease><Blood Vessels><Blood monocyte><Bone Marrow><Bone Marrow Reticuloendothelial System><CRISPR editing screen><CRISPR screen><CRISPR-based screen><CRISPR/Cas9 screen><Cardiovascular><Cardiovascular Body System><Cardiovascular Organ System><Cardiovascular system><Cell Body><Cells><Clinical><Cytokinesis><Cytoplasmic Division><DNMT3a><Data><Data Set><Event><Excision><Extirpation><Genes><Genetic Alteration><Genetic Change><Genetic defect><Guide RNA><Heart Vascular><Hematopoiesis><Hematopoietic Cellular Control Mechanisms><Histologic><Histologically><Human><Impairment><In Situ><In Vitro><Inflammation><JAK-2><JAK2><JAK2 gene><JAK2 protein><Janus kinase 2><Knock-out><Knockout><Knowledge><Lesion><Lipids><MYC Family Protein><MYC Protein><Macrophage><Maps><Marrow monocyte><Mediating><Membrane><Messenger RNA><Mice><Mice Mammals><Modern Man><Molecular><Mononuclear><Murine><Mus><Mutation><Myelogenous><Myeloid><Mφ><Necrosis><Necrotic><Patients><Phagocytes><Phagocytic Cell><Phenotype><Polyploid><Polyploidy><Process><Proliferating><Proteins><Removal><Residual><Residual state><Resolution><Risk><Risk Reduction><Role><Short interfering RNA><Small Interfering RNA><Stromal Cells><Surgical Removal><Testing><Therapeutic><Thick><Thickness><Transplantation><Tyrosine-Protein Kinase JAK2><Work><amebocyte><atheromatosis><atherosclerosis plaque><atherosclerotic disease><atherosclerotic lesions><atherosclerotic plaque><atherosclerotic vascular disease><biobank><biorepository><blood cell formation><cardiovascular disease risk><cardiovascular disorder risk><circulatory system><clustered regularly interspaced short palindromic repeats screen><gRNA><genome mutation><genome scale><genome-wide><genomewide><hDNA methyltransferase 3a><in vivo><insight><knock-down><knockdown><lentiviral-mediated><lipid based nanoparticle><lipid nanoparticle><mRNA><membrane structure><monocyte><nano particle delivery><nanoparticle delivered><nanoparticle delivery><new approaches><new drug treatments><new drugs><new pharmacological therapeutic><new therapeutics><new therapy><next generation therapeutics><novel><novel approaches><novel drug treatments><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel strategies><novel strategy><novel therapeutics><novel therapy><protein function><reduce risk><reduce risks><reduce that risk><reduce the risk><reduce these risks><reduces risk><reduces the risk><reducing risk><reducing the risk><resection><resolutions><risk-reducing><scRNA-seq><siRNA><single cell RNA-seq><single cell RNAseq><single cell expression profiling><single cell transcriptomic profiling><single-cell RNA sequencing><social role><transcriptomics><transplant><vascular><vulnerable plaque><western diet><western-style diet><western-type diet>