This Project Grant award, totaling $441,098.00, was provided by the National Institute of Allergy and Infectious Diseases (NIAID) under the Allergy and Infectious Diseases Research Federal Grant Program (CFDA 93.855). The grant aims to investigate the antagonistic relationship between the transcription factors IRF4 and BACH2 in regulating germinal center B cell fates and promoting lymphomagenesis. The research project, with a performance period from July 2025 to June 2027, will use transgenic...
This $693,942 National Institutes of Health National Heart Lung and Blood Institute Project Grant funds research at Northwestern University aimed at elucidating epigenetic modifiers of regulatory T cell function following viral pneumonia. The goal is to establish causal links between DNA methyltransferase activity, the DNMT adapter UHRF1, and DNA hypermethylation signatures in regulatory T cells during aging and their impaired reparative function after severe viral pneumonia. Through three...
This $393,750.00 Project Grant award from the National Institute of General Medical Sciences (NIGMS) under the Biomedical Research and Research Training program (CFDA 93.859) will fund a 5-year research project to explore the fundamental cellular mechanisms driving cellular senescence in macrophages. The key objectives of this research project are to gain a deeper understanding of the cellular and molecular mechanisms underlying senescent macrophage biology. This includes investigating the roles...
This $677,600 Project Grant award from the National Heart, Lung, and Blood Institute (CFDA 93.837 Cardiovascular Diseases Research) aims to gain a mechanistic understanding of erythroid progenitor (EP) self-renewal, both in vitro and in vivo. The primary goals are to: Test the hypothesis that the BMI1/RING1B chromatin modulators regulate human self-renewing erythroblast (SRE) self-renewal through epigenetic control of transcription and cholesterol homeostasis. Test the hypothesis that...
This Project Grant award from the National Heart, Lung, and Blood Institute (NHLBI) under the Cardiovascular Diseases Research program (CFDA 93.837) provides $686,640 to The Trustees of Columbia University in the City of New York, Health Sciences Division, to conduct research focused on enhancing macrophage efferocytosis as a potential therapeutic strategy for atherosclerotic cardiovascular disease (ACVD). The key objectives are to: 1) Determine how knocking out the ILRUN gene can enhance...
This Project Grant award from the National Heart, Lung, and Blood Institute (NHLBI) under CFDA 93.837 - Cardiovascular Diseases Research provides $784,206 to investigate the role of the CSF-1/CSF-1R axis in myocardial infarction (MI) repair and remodeling. The award to Albert Einstein College of Medicine will fund research to: 1) examine the in vivo effects of macrophage-specific CSF-1R activation on cardiac repair and remodeling after MI; 2) investigate the role of fibroblast-derived CSF-1 in...
This Project Grant award of $715,180, provided by the National Heart, Lung, and Blood Institute (CFDA 93.837 - Cardiovascular Diseases Research) to Baylor College of Medicine, aims to understand the mechanisms driving persistent inflammation in thoracic aortic aneurysms and dissections (ATAAD). The primary objectives are to: Determine the epigenetic signatures and duration of "trained immunity" in monocytes/macrophages within the aortic wall and bone marrow in ATAAD. This will...
This Project Grant award of $735,085 from the National Heart, Lung, and Blood Institute (CFDA 93.837 - Cardiovascular Diseases Research) supports research at Case Western Reserve University to investigate modulating the Heat Shock Transcription Factor 1 (HSF1) as a means to transform detrimental age-related clonal hematopoiesis (CH) into a state favoring normal blood cell production while preventing CH progression. The research aims to understand how deleting HSF1 along with the CH-associated...
This federal Project Grant award from the National Institute of Allergy and Infectious Diseases (NIAID), under the Allergy and Infectious Diseases Research program (CFDA 93.855), provides $831,755 over 5 years to New York University (NYU) to conduct research on the role of lung-resident macrophage subsets in regulating type 2 immune responses and trained immunity. The research aims to elucidate the distinct functions of different macrophage populations, particularly nerve- and...
This Project Grant award from the National Heart, Lung, and Blood Institute (NHLBI) under CFDA 93.837 - Cardiovascular Diseases Research supports a study on the role of branched-chain amino acids in regulating inflammasome-mediated host defense against respiratory pathogens. The $153,512 award will fund research to mechanistically dissect how branched-chain amino acid metabolism and sensing converge to transcriptionally and translationally drive inflammasome function and IL-1 cytokine release....
BACH1 AS A NOVEL PIONEER REPRESSOR IN MACROPHAGES: IMPACT ON HOMEOSTASIS AND INFLAMMATION - PROJECT SUMMARY TRANSCRIPTION PLAYS AN OVERSIZED ROLE IN DETERMINING PROPER INFLAMMATORY RESPONSE IN IMMUNE CELLS SUCH AS MACROPHAGES (MF). TRANSCRIPTIONAL MASTER REGULATORS OF MFS ARE THOUGHT TO BE THE MAIN DRIVERS OF CHROMATIN REPROGRAMMING DURING MYELOID CELL DIFFERENTIATION, POLARIZATION AND ACTIVATION. HOWEVER, RECENT STUDIES HAVE EXPANDED THIS "DEVELOPMENTAL TF-CENTRIC" MODEL AND SUGGEST THAT SIGNAL-DEPENDENT TFS, IN PARTICULAR REPRESSORS, LIKELY TO HAVE A PIONEER ROLE IN THE SHAPING THE MF EPIGENOME. SUCH AN EXPANDED MODEL ALSO PREDICTS THAT ACTIVE TRANSCRIPTIONAL REPRESSION AND CHROMATIN BOOKMARKING BY SIGNAL-DEPENDENT MASTER REGULATORS IS A KEY MECHANISM FOR THE SAFEGUARDING THE ENHANCER REPERTOIRE AND PROPER DEPLOYMENT AND RESOLUTION OF AN INFLAMMATORY RESPONSE. RECENTLY, WE IDENTIFIED SUCH A SIGNAL-DEPENDENT TF, THE HEME- REGULATED REPRESSOR BACH1 (BTB DOMAIN AND CNC HOMOLOG 1), WITH PROPERTIES OF A MASTER REGULATOR OF THE MF EPIGENOME. OUR PRELIMINARY DATA IS CONTRARY TO CURRENT DOGMA ABOUT THIS TF AND ALSO CHALLENGING THE CURRENT VIEW OF INFLAMMATORY GENE REGULATION. THE CENTRAL HYPOTHESIS OF THIS PROPOSAL IS THAT BACH1 ACTS AS A PIONEERING REPRESSOR, SIGNAL-DEPENDENT MASTER REGULATOR AND AN EPIGENOMIC SAFEGUARD THAT PLAYS A KEY ROLE DURING MACROPHAGE DIFFERENTIATION AND POLARIZATION/SPECIFICATION BY ACTIVELY REPRESSING ENHANCERS, GENOME-WIDE, CONTROLLING INFLAMMATORY, METABOLIC AND DIFFERENTIATION-SPECIFIC GENES WITH EFFECTS ON THE BASELINE, AMPLITUDE AND PROPER KINETICS OF THE INFLAMMATORY GENE EXPRESSION. WE PROPOSE THREE INTERRELATED AND INTEGRATED BUT INDEPENDENT SPECIFIC AIMS IN WHICH WE WILL COMBINE NEW GENETIC MOUSE MODELS WITH CUTTING EDGE MOLECULAR BIOLOGY APPROACHES TO ESTABLISH BACH1 AS A CRITICAL MODULATOR OF MF INFLAMMATORY GENE EXPRESSION AND SUBTYPE SPECIFICATION. OUR APPROACHES AIM TO PROVIDE DEEP MECHANISTIC INSIGHTS ON BACH1 FUNCTION ON ACTIVE REPRESSION, PIONEERING, TRANSCRIPTIONAL ACTIVATION, 3D CHROMATIN STRUCTURE AND INFLAMMATORY GENE EXPRESSION AND ESTABLISH BACH1 AS A NOVEL SIGNAL-DEPENDENT MASTER REGULATOR AND AS PART OF THE CORE HARDWIRED TRANSCRIPTIONAL CIRCUIT OF MFS. MOREOVER, RESULTS FROM THE PROPOSED WORK ARE EXPECTED TO PUSH THE FIELD FORWARD BY PROVIDING A MECHANISTIC FRAMEWORK OF HOW HEME, A MOLECULE VITAL FOR LIFE AND CELL METABOLISM BUT CYTOTOXIC WHEN IN EXCESS, CAN AFFECT THE DIFFERENTIATION AND INFLAMMATORY POTENTIAL OF MFS.