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Principal Investigator: Victor J. Thannickal
Organization: TULANE UNIVERSITY OF LOUISIANA
Fiscal Year: 2024
Award: $609,272
Funding agency: National Heart Lung and Blood Institute
PROJECT SUMMARY
Cell metabolism regulates epigenetic reprograming to determine cellular identity and fate.
Intermediary metabolites serve as essential cofactors for epigenetic modifying enzymes. Epithelial-
mesenchymal crosstalk is critical for the maintenance of adult tissues/organs and in regenerative
responses to tissue injury. In the lung, alveolar maintenance and regeneration are orchestrated by the
interaction of alveolar type 2 (AT2) cells, a facultative stem/progenitor cell population, with the
adjacent mesenchyme that contributes to “niche” support of the regenerating epithelium. These
homeostatic type 2 niche-supporting stromal cells (T2NSCs) may transition to pathological
mesenchymal states/fates during lung injury-repair.
We have identified a metabolic enzyme, nicotinamide N-methyltransferase (NNMT), that regulates
the plasticity of tissue-resident fibroblasts (FBs) and the transition of lipofibroblasts (lipo-FBs) into
myofibroblasts (myo-FBs). NNMT catalyzes the N-methylation of nicotinamide and other pyridine
compounds; by utilizing the universal methyl donor, SAM in this reaction, NNMT functions as a
“methyl sink” in many tissues, while also depleting cellular NAD+ levels. Our data indicate that NNMT
is upregulated in lung mesenchymal cells of idiopathic pulmonary fibrosis (IPF), and is induced by the
pro-fibrotic cytokine, transforming growth factor-β1, in human lung fibroblasts. NNMT functions as a
critical switch from lipo-FB to myo-FB differentiation that acquire apoptosis resistance, thus impairing
fibrosis resolution.
In this project we will test the hypothesis that metabolic-epigenetic reprogramming of activated
stromal T2NSCs by targeting NNMT potentiates lung regenerative capacity and facilitates fibrosis
resolution by augmenting cellular levels of NAD+ and/or SAM. Our specific aims are to: (1) identify
T2NSCs subpopulations and characterize their regulation by NNMT; (2) determine mechanisms by
which NNMT regulates lipo-FB to myo-FB transition; and (3) determine whether targeting NNMT
accelerates fibrosis resolution in an animal model of lung injury-induced fibrosis. A combination of
bulk and single-cell RNA-seq, ATAC-seq, metabolomics, bioenergetics, and epigenetic profiling in 3D
alveolospheres, IPF lung FBs, and an in-vivo lung injury model will be employed. The studies
proposed in this grant application will advance the field by identifying a critical regulatory switch in
lipo-FB to myo-FB differentiation, linking metabolism to epigenetics by an enzyme that controls both
cellular bioenergetics and protein methylation, defining a therapeutic strategy that achieves fibrosis
resolution/reversal in established lung fibrosis, and elucidating a functional role of alveolar stem cell
niche-supporting fibroblasts in stem cell rejuvenation and tissue regeneration.
Terms: <1H-Purin-6-amine><21+ years old><3-D><3-Dimensional><3-Pyridinecarboxamide><3D><ATAC sequencing><ATAC-seq><ATACseq><Acceleration><Acetyl CoA><Acetyl Coenzyme A><Acetylation><Address><Ademetionine><Adenine><AdoMet><Adult><Adult Human><Alveolar><Animal Model><Animal Models and Related Studies><Apoptosis><Apoptosis Pathway><Applications Grants><Assay for Transposase-Accessible Chromatin using sequencing><Bioenergetics><Body Tissues><Cell Body><Cell Function><Cell Physiology><Cell Process><Cells><Cellular Function><Cellular Metabolic Process><Cellular Physiology><Cellular Process><Chromatin><Data><Development><Dihydronicotinamide Adenine Dinucleotide><Diphosphopyridine Nucleotide><Enzyme Gene><Enzymes><Epigenetic><Epigenetic Change><Epigenetic Mechanism><Epigenetic Process><Epithelium><Failure><Fibroblasts><Fibrosing Alveolitis><Fibrosis><Grant Proposals><Human><Impairment><Intermediary Metabolism><Link><Lung><Lung Respiratory System><Lung Tissue Fibrosis><Lung damage><Maintenance><Mammalia><Mammals><Mesenchymal><Mesenchymas><Mesenchyme><Metabolic><Metabolic Pathway><Metabolic Processes><Metabolism><Methylation><Modeling><Modern Man><Molecular Configuration><Molecular Conformation><Molecular Stereochemistry><Myofibroblast><Nadide><Natural regeneration><Niacinamide><Nicotinamide><Nicotinamide N-Methyltransferase><Nicotinamide adenine dinucleotide><Nicotinamide-Adenine Dinucleotide><Nicotinamidum><Nicotinic acid amide><Nicotylamide><Organ><Organogenesis><Organoids><Pathologic><Pattern><Pellagra-Preventing Factor><Phenotype><Phosphorylation><Physiologic><Physiological><Progenitor Cells><Programmed Cell Death><Protein Methylation><Protein Phosphorylation><Pulmonary Body System><Pulmonary Fibrosis><Pulmonary Organ System><Reaction><Regeneration><Regenerative capacity><Regenerative response><Regulation><Rejuvenation><Resistance><Resolution><Respiratory System><Respiratory Tracts><Respiratory tract structure><Role><S-Adenosylhomocysteine><S-Adenosylmethionine><S-acetate Coenzyme A><S-adenosyl methionine><S-adenosyl-methionine><SAMe><Slice><Stromal Cells><Subcellular Process><Testing><Therapeutic><Tissues><Transforming Growth Factors><Tumor Growth Factors><Vitamin B 3><Vitamin B3><Vitamin B4><Vitamin PP><adulthood><assay for transposase accessible chromatin followed by sequencing><assay for transposase accessible chromatin seq><assay for transposase accessible chromatin sequencing><assay for transposase-accessible chromatin with sequencing><cell behavior><cell metabolism><cellular behavior><cellular metabaolism><cofactor><conformation><conformational><conformational state><conformationally><conformations><developmental><diffuse interstitial pulmonary fibrosis><epigenetic profiling><epigenetically><epithelium regeneration><fibrosis in the lung><histone methylation><histone modification><idiopathic pulmonary fibrosis><in vivo><injury and repair><injury to tissue><lung fibrosis><lung injury><metabolism measurement><metabolomics><metabonomics><model of animal><nicotinamide methylase><nicotinamide methyltransferase><nicotinamide-S-adenosylmethionine methyltransferase><pharmacologic><profibrotic cytokine><progenitor cell niche><progenitor cell population><progenitor niche><progenitor population><programs><pulmonary><pulmonary damage><pulmonary injury><pulmonary tissue damage><pulmonary tissue injury><pyridine><regenerate><regenerate epithelium><regenerate new tissue><regenerate tissue><regenerating damaged tissue><regenerating tissue><regeneration ability><regeneration capacity><regeneration potential><regeneration response><regenerative><regenerative potential><resistant><resolutions><s-adenosyl-l-methionine><scRNA-seq><single cell RNA-seq><single cell RNAseq><single cell expression profiling><single cell transcriptomic profiling><single-cell RNA sequencing><social role><stem and progenitor cell niche><stem and progenitor cell population><stem cell niche><stem cell population><stem cells><three dimensional><tissue injury><tissue regeneration><tissue regrowth><tissue renewal><tissue specific regeneration><transforming growth factors Animal growth regulators><triphosphate><tripolyphosphate>