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Principal Investigator: Jeong H Yun
Organization: BRIGHAM AND WOMEN'S HOSPITAL
Fiscal Year: 2024
Award: $169,560
Funding agency: National Heart Lung and Blood Institute
Project Summary
Chronic obstructive pulmonary disease (COPD), primarily caused by cigarette smoking, is the third leading cause
of death in the United States. Remarkably, individuals with similar smoking histories have different susceptibility
to develop the disease, and patients display a variable degree of clinical manifestations. Genetic factors may
account for these differences, but the functional, cellular and molecular basis of the variation remains to be
explored. This project aims to bridge knowledge from the genome-wide association studies (GWAS) of COPD
to the pathophysiological mechanisms of the disease by utilizing the observations that (1) inflammatory response
is one of the most prominent differences upon cigarette smoke exposure and (2) a genetic animal model based
on GWAS recapitulates the prominent features of a severe inflammatory response in COPD.
Specifically, we found that genetic mouse models deficient of Hedgehog interacting protein (HHIP), a gene
consistently associated with COPD in GWAS, not only recapitulate robust emphysema susceptibility, but display
a strong inflammatory phenotype similar to human COPD. In particular, an increase in activated CD8+T cells is
observed along the course of emphysema development. Preliminary studies using single cell RNA sequencing
showed that Hhip expression is restricted to lung fibroblasts and absent from immune cells including the
lymphocytes. Moreover, Hhip deficient lung fibroblasts have increased expression of cytokines known to activate
CD8+T cells. These findings led us to hypothesize that reduced HHIP expression in lung fibroblasts leads to an
increase in cytokines and activation of CD8+T cells, and these activated CD8+T cells play a major role in
parenchymal destruction (emphysema). We propose to investigate this hypothesis by the following specific aims:
1. Determine whether CD8+T cell activation depends on Hhip in lung fibroblasts, 2. Determine the functional
importance of lymphocytic activation induced by Hhip-deficiency in smoke-induced lung inflammation and 3.
Determine the relationships between HHIP risk locus and pulmonary lymphocytic inflammation in human
subjects.
Dr. Yun will perform this work under the mentorship of Dr. Hersh, an expert in the field of COPD genomics, Dr.
Zhou, an expert in the field of functional genomics, and Dr. Silverman, an expert in COPD genetic epidemiology.
With the guidance of her mentors and scientific advisory committee composed of distinguished scientists with
expertise related to key areas of this proposal including lung immunology, functional validation and biostatistics,
Dr. Yun has developed a comprehensive five-year training program. This K08 award will support Dr. Yun to
develop the skills needed to become an independent physician-scientist with the long-term goal of understanding
how genetic variation modifies COPD by bridging human ‘omics data and functional validation of candidate
genes.
Terms: <(TNF)-α><Activated Lymphocyte><Active Follow-up><Address><Adoptive Transfer><Advisory Committees><Animal Genetics><Animal Model><Animal Models and Related Studies><Area><Award><Biometrics><Biometry><Biostatistics><Blast Transformation><Blastogenesis><CD8 Cell><CD8 T cells><CD8 lymphocyte><CD8+ T cell><CD8+ T-Lymphocyte><CD8-Positive Lymphocytes><CD8-Positive T-Lymphocytes><COPD><Cachectin><Candidate Disease Gene><Candidate Gene><Cause of Death><Cell Body><Cell Protection><Cells><Chronic Obstruction Pulmonary Disease><Chronic Obstructive Lung Disease><Chronic Obstructive Pulmonary Disease><Clinical><Cytoprotection><Data><Data Set><Development><Diathesis><Disease><Disease susceptibility><Disorder><Emphysema><Erinaceidae><Fibroblasts><Frequencies><GWA study><GWAS><Gene Expression><Genes><Genetic><Genetic Diversity><Genetic Risk><Genetic Variation><Genetic predisposing factor><Genomics><Genotype><Goals><Hedgehogs><Heterogeneity><Histologic><Histologically><Human><IFN-Gamma><IFN-Gamma-Inducing Factor Gene><IFN-g><IFN-gamma-Inducing Factor><IFN-γ><IFNG><IFNγ><IGIF><IGIF Gene><IL-1 Gamma><IL-1 Gamma Gene><IL-18><IL-18 Gene><IL-1g><IL-1g Gene><IL18><IL18 Protein><IL18 gene><IL1F4><IL1F4 Gene><Immune><Immune Cell Activation><Immune Diseases><Immune Disorders><Immune Dysfunction><Immune Interferon><Immune System Diseases><Immune System Disorder><Immune System Dysfunction><Immune System and Related Disorders><Immune response><Immunes><Immunochemical Immunologic><Immunodeficiency and Immunosuppression Disorders><Immunologic><Immunologic Diseases><Immunological><Immunological Diseases><Immunological Dysfunction><Immunological System Dysfunction><Immunological response><Immunologically><Immunologics><Immunology><In Vitro><Individual><Infiltration><Inflammation><Inflammation Mediators><Inflammatory><Inflammatory Response><Interferon Gamma><Interferon Type II><Interferon-Gamma-Inducing Factor Gene><Interferon-gamma-Inducing Factor><Interleukin 18 (Interferon-Gamma-Inducing Factor)><Interleukin 18 (Interferon-Gamma-Inducing Factor) Gene><Interleukin 18 Proprotein><Interleukin 18 Proprotein Gene><Interleukin-1 Gamma><Interleukin-1 Gamma Gene><Interleukin-18><Interleukin-18 Precursor><Interleukin-18 Precursor Gene><KO mice><Knock-out Mice><Knockout Mice><Knowledge><Lead><Lung><Lung Diseases><Lung Inflammation><Lung Parenchyma><Lung Respiratory System><Lung Tissue><Lymphatic cell><Lymphoblast Transformation><Lymphocyte><Lymphocyte Activation><Lymphocyte Stimulation><Lymphocyte Transformation><Lymphocytic><Lymphoid Follicle><MGC12320><MGC12320 Gene><MMPs><Macrophage-Derived TNF><Matrix Metalloproteinases><Mediating><Mentors><Mentorship><Mice><Mice Mammals><Modern Man><Molecular><Monocyte-Derived TNF><Murine><Mus><Null Mouse><Outcome><Pathogenesis><Pathology><Patients><Pb element><Phenotype><Physicians><Play><Pneumonitis><Predisposition><Process><Protein Deficiency><Proteins><Pulmonary Diseases><Pulmonary Disorder><Pulmonary Emphysema><Pulmonary Inflammation><Reporting><Research><Research Proposals><Risk><Risk-associated variant><Role><Sampling><Scientist><Shapes><Single cell seq><Slice><Smoke><Smoker><Smoking><Smoking History><Structure of parenchyma of lung><Susceptibility><System><T cell infiltration><T-Cell Activation><T8 Cells><T8 Lymphocytes><TNF><TNF A><TNF Alpha><TNF gene><TNF-α><TNFA><TNFα><Task Forces><Tissue Sample><Training><Training Programs><Tumor Necrosis Factor><Tumor Necrosis Factor-alpha><United States><Validation><Variant><Variation><Work><activate T cells><active followup><advisory team><biobank><biorepository><candidate validation><chronic inflammatory lung disease><chronic obstructive pulmonary disorder><cigarette smoke exposure><cigarette smoking><cigarette use><cohort><cytokine><cytoprotective><deficiency of protein><develop therapy><developmental><disease of the lung><disease risk><disorder of the lung><disorder risk><emphysematous><exposure to cigarette smoke><follow up><follow-up><followed up><followup><functional genomics><genetic epidemiologic study><genetic epidemiology><genetic risk factor><genome wide association><genome wide association scan><genome wide association studies><genome wide association study><genomewide association scan><genomewide association studies><genomewide association study><global gene expression><global transcription profile><heavy metal Pb><heavy metal lead><host response><human subject><immune activation><immune system response><immunoresponse><in vivo><inflammatory mediator><inherited factor><insight><intervention development><lFN-Gamma><liability to disease><lung disorder><lymph cell><migration><model of animal><mouse model><murine model><new drug target><new druggable target><new pharmacotherapy target><new therapeutic target><new therapy target><novel drug target><novel druggable target><novel pharmacotherapy target><novel therapeutic target><novel therapy target><overexpress><overexpression><pack/year><protein expression><pulmonary><response><risk allele><risk gene><risk genotype><risk loci><risk locus><risk variant><scRNA-seq><single cell RNA-seq><single cell RNAseq><single cell expression profiling><single cell next generation sequencing><single cell sequencing><single cell transcriptomic profiling><single-cell RNA sequencing><skills><smoking exposure><social role><therapy development><transcriptome><treatment development><validations><whole genome association analysis><whole genome association studies><whole genome association study>