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Principal Investigator: Rajeev Dhupar
Organization: VETERANS HEALTH ADMINISTRATION
Fiscal Year: 2024
Funding agency: Veterans Affairs
Deployment related respiratory exposures (DRREs) during the Gulf War are now presumed to be linked to the
development of lung cancer and other respiratory diseases. Recently, we employed a unique mouse model of
experimental burn pit-type airborne toxin exposures and found that this induced prolonged inflammation and
epigenetic alterations regulating key cancer associated pathways in alveolar macrophages. Unfortunately,
there is limited research that examines the link between toxic respiratory exposures and an increased risk for
developing lung cancer. Our objective is to determine the pathobiology of how DRREs predispose Veterans to
lung cancer. To do this, we will (1) identify cancer-associated epigenetic alterations in lung tissue from
Veterans deployed during the Gulf War who developed lung cancer, (2) employ digital spatial profiling to
generate a transcriptional atlas of effected lung tissues from Gulf War Veterans to inform immune-mediated
remodeling of the lung, (3) use a mouse model to determine how aerosolized gulf war toxins increase
susceptibility to lung cancer, and (4) reverse the harmful epigenetic changes in cancer promoting pathways in
3D lung culture systems and primary cells from Veterans and following experimental aerosolized toxin
exposures in mice. We will use this information to define the epigenetic alterations from DRREs that promote
lung cancer, develop a grading system based on durable epigenetic marks identified in immune cells, and
identify targetable epigenetic changes to potentially reduce the risk for developing lung cancer. Ultimately, if
this project is successful we will better understand the mechanisms that underlie the development of lung
cancer for deployed Gulf War Veterans. This will improve options for therapy and possibly a way to screen
Veterans for an increased risk for developing lung cancer. Importantly, the findings may have broader
implications for military service members deployed to the Persian Gulf, Southwest Asia and Afghanistan, as
well as those in similar theatres of operation in the future.
Terms: <3-D><3-Dimensional><3D><4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone><ATAC sequencing><ATAC-seq><ATACseq><Address><Afghanistan><Airway health><Alveolar Macrophages><Asia><Assay for Transposase-Accessible Chromatin using sequencing><Atlases><Burn injury><Burns><Cancer Cause><Cancer Causing Agents><Cancer Etiology><Cancers><Carcinogens><Caring><Cell Body><Cells><Chemicals><Chronic><Cristobalite><Crude Oil><DNA Methyltransferase><DNA Modification Methylases><DNA Modification Methyltransferases><DNA-Methyltransferases><Data><Data Bases><Databases><Development><Diagnosis><Dnmt><Emphysema><Endothelium><Enzyme Gene><Enzymes><Epigenetic><Epigenetic Change><Epigenetic Mechanism><Epigenetic Process><Epithelium><Experimental Models><Exposure to><Expression Signature><Fibroblasts><Fire - disasters><Fires><Future><GW veteran><Gene Combinations><Gene Expression Profile><Gene Transcription><Genes><Genetic><Genetic Transcription><Genomics><Goals><Gulf War><Gulf War veteran><HDAC Agent><HDAC inhibitor><Histone Deacetylase Inhibitor><Histone deacetylase inhibition><Human><Immune><Immunes><Immunochemical Immunologic><Immunologic><Immunological><Immunologically><Immunologics><Incidence><Inflammation><Inflammatory><Inhalation><Inhaling><Institute of Medicine><Institute of Medicine (U.S.)><Investigation><Link><Lung><Lung Inflammation><Lung Parenchyma><Lung Respiratory System><Lung Tissue><Macrophage><Malignant Neoplasms><Malignant Tumor><Malignant Tumor of the Lung><Malignant neoplasm of lung><Mediating><Mice><Mice Mammals><Modern Man><Modification><Modification Methylases><Murine><Mus><Mφ><NAS/IOM><NNK><Oils><Oncogens><Operation Desert Shield><Operation Desert Storm><Outcome><Particulate><Particulate Matter><Pathology><Pathway interactions><Persian Gulf><Pesticides><Petroleum><Phagocytes><Phagocytic Cell><Pneumonitis><Predisposition><Program Development><Pulmonary Cancer><Pulmonary Emphysema><Pulmonary Inflammation><Pulmonary Macrophages><Pulmonary Pathology><Pulmonary malignant Neoplasm><RNA Expression><RNA Seq><RNA sequencing><RNAseq><Rationalization><Research><Research Specimen><Research Support><Respiratory Disease><Respiratory System Disease><Respiratory System Disorder><Risk><Risk Assessment><Risk Reduction><Role><Sand><Services><Silica><Silicon Dioxide><Site-Specific DNA-methyltransferase><Slice><Specimen><Structure of parenchyma of lung><Susceptibility><System><Tobacco-Associated Carcinogen><Toxicant exposure><Toxin><Transcription><Tridymite><Veterans><aerosolized><amebocyte><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><burn pit><burned><cancer initiation><cancer registry><cancer risk><carcinogenicity><cigarette smoke><combustion by-products><combustion product><data base><developmental><diagnostic criteria><digital><emphysematous><epigenetically><epithelial to mesenchymal transition><experience><fire><gene expression pattern><gene expression signature><improved><in vivo><insight><lung cancer><lung development><lung pathology><malignancy><military member><military service><mouse model><murine model><neoplasm registry><neoplasm/cancer><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><oncogenic agent><operation><operations><pathway><petroleum oil><pharmacologic><prevent><preventing><pulmonary><reduce risk><reduce risks><reduce that risk><reduce the risk><reduce these risks><reduces risk><reduces the risk><reducing risk><reducing the risk><respiratory><respiratory health><response><risk-reducing><screening><screenings><service member><social role><three dimensional><tobacco carcinogen><tobacco related carcinogen><tobacco specific carcinogen><toxic exposure><transcriptional profile><transcriptional signature><transcriptome sequencing><transcriptomic sequencing><transcriptomics><tumor initiation>