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High burden of clonal hematopoiesis in first responders exposed to the World Trade Center disaster

Jasra, Sakshi; Giricz, Orsi; Zeig-Owens, Rachel; Pradhan, Kith; Goldfarb, David G; Barreto-Galvez, Angelica; Silver, Alexander J; Chen, Jiahao; Sahu, Srabani; Gordon-Mitchell, Shanisha; Choudhary, Gaurav S; Aluri, Srinivas; Bhagat, Tushar D; Shastri, Aditi; Bejan, Cosmin A; Stockton, Shannon S; Spaulding, Travis P; Thiruthuvanathan, Victor; Goto, Hiroki; Gerhardt, Jeannine; Haider, Syed Hissam; Veerappan, Arul; Bartenstein, Matthias; Nwankwo, George; Landgren, Ola; Weiden, Michael D; Lekostaj, Jacqueline; Bender, Ryan; Fletcher, Frederick; Greenberger, Lee; Ebert, Benjamin L; Steidl, Ulrich; Will, Britta; Nolan, Anna; Madireddy, Advaitha; Savona, Michael R; Prezant, David J; Verma, Amit
The terrorist attacks on the World Trade Center (WTC) created an unprecedented environmental exposure to aerosolized dust, gases and potential carcinogens. Clonal hematopoiesis (CH) is defined as the acquisition of somatic mutations in blood cells and is associated with smoking and exposure to genotoxic stimuli. Here we show that deep targeted sequencing of blood samples identified a significantly higher proportion of WTC-exposed first responders with CH (10%; 48 out of 481) when compared with non-WTC-exposed firefighters (6.7%; 17 out of 255; odds ratio, 3.14; 95% confidence interval, 1.64-6.03; P = 0.0006) after controlling for age, sex and race/ethnicity. The frequency of somatic mutations in WTC-exposed first responders showed an age-related increase and predominantly affected DNMT3A, TET2 and other CH-associated genes. Exposure of lymphoblastoid cells to WTC particulate matter led to dysregulation of DNA replication at common fragile sites in vitro. Moreover, mice treated with WTC particulate matter developed an increased burden of mutations in hematopoietic stem and progenitor cell compartments. In summary, the high burden of CH in WTC-exposed first responders provides a rationale for enhanced screening and preventative efforts in this population.
PMID: 35256801
ISSN: 1546-170x
CID: 5180942

Human Rhinovirus Infection of the Respiratory Tract Affects Sphingolipid Synthesis

Wasserman, Emily; Gomi, Rika; Sharma, Anurag; Hong, Seunghee; Bareja, Rohan; Gu, Jinghua; Balaji, Uthra; Veerappan, Arul; Kim, Benjamin I; Wu, Wenzhu; Heras, Andrea; Perez-Zoghbi, Jose; Sung, Biin; Gueye-Ndiaye, Seyni; Worgall, Tilla S; Worgall, Stefan
The 17q21 asthma susceptibility locus includes asthma risk alleles associated with decreased sphingolipid synthesis, likely resulting from increased expression of ORMDL3. ORMDL3 inhibits serine-palmitoyl transferase (SPT), the rate limiting enzyme of de novo sphingolipid synthesis. There is evidence that decreased sphingolipid synthesis is critical to asthma pathogenesis. Children with asthma and 17q21 asthma risk alleles display decreased sphingolipid synthesis in blood cells. Reduced SPT activity results in airway hyperreactivity, a hallmark feature of asthma. 17q21 asthma risk alleles are also linked to childhood infections with human rhinovirus (RV). This study evaluates the interaction of RV with the de novo sphingolipid synthesis pathway, and the alterative effects of concurrent SPT inhibition in SPT-deficient mice and human airway epithelial cells. In mice, RV infection shifted lung sphingolipid synthesis gene expression to a pattern that resembles genetic SPT deficiency, including decreased expression of Sptssa, a small SPT subunit. This pattern was pronounced in lung EpCAM+ epithelial cells and reproduced in human bronchial epithelial cells. RV did not affect Sptssa expression in lung CD45+ immune cells. RV increased sphingolipids unique to the de novo synthesis pathway in mouse lung and human airway epithelial cells. Interestingly, these de novo sphingolipid species were reduced in the blood of RV infected, wild-type mice. RV exacerbated SPT-deficiency-associated airway hyperreactivity. Airway inflammation was similar in RV-infected wild-type and SPT deficient mice. This study reveals the effects of RV infection on the de novo sphingolipid synthesis pathway, elucidating a potential mechanistic link between 17q21 asthma risk alleles and rhinoviral infection.
PMID: 34851798
ISSN: 1535-4989
CID: 5069512

Alveolar Macrophages and Epithelial Cells Express RAGE in a Murine [Meeting Abstract]

Veerappan, A; Sunseri, M; Young, IR; Nolan, A
ORIGINAL:0015553
ISSN: 1535-4970
CID: 5203492

Tandem Mass Tagging Based Identification of Proteome Signatures for Reductive Stress Cardiomyopathy

Sunny, Sini; Jyothidasan, Arun; David, Cynthia L; Parsawar, Krishna; Veerappan, Arul; Jones, Dean P; Pogwizd, Steven; Rajasekaran, Namakkal S
Nuclear factor erythroid 2-related factor 2 (NRF2), a redox sensor, is vital for cellular redox homeostasis. We reported that transgenic mice expressing constitutively active Nrf2 (CaNrf2-TG) exhibit reductive stress (RS). In this study, we identified novel protein signature for RS-induced cardiomyopathy using Tandem Mass Tag (TMT) proteomic analysis in heart tissues of TG (CaNrf2-TG) mice at 6-7 months of age. A total of 1,105 proteins were extracted from 22,544 spectra. About 560 proteins were differentially expressed in TG vs. NTg hearts, indicating a global impact of RS on the myocardial proteome. Over 32 proteins were significantly altered in response to RS -20 were upregulated and 12 were downregulated in the hearts of TG vs. NTg mice, suggesting that these proteins could be putative signatures of RS. Scaffold analysis revealed a clear distinction between TG vs. NTg hearts. The majority of the differentially expressed proteins (DEPs) that were significantly altered in RS mice were found to be involved in stress related pathways such as antioxidants, NADPH, protein quality control, etc. Interestingly, proteins that were involved in mitochondrial respiration, lipophagy and cardiac rhythm were dramatically decreased in TG hearts. Of note, we identified the glutathione family of proteins as the significantly changed subset of the proteome in TG heart. Surprisingly, our comparative analysis of NGS based transcriptome and TMT-proteome indicated that ~50% of the altered proteins in TG myocardium was found to be negatively correlated with their transcript levels. In association with the altered proteome the TG mice displayed pathological cardiac remodeling.
PMCID:9234166
PMID: 35770227
ISSN: 2297-055x
CID: 5281262

Author Correction: World Trade Center-Cardiorespiratory and Vascular Dysfunction: Assessing the Phenotype and Metabolome of a Murine Particulate Matter Exposure Model

Veerappan, Arul; Oskuei, Assad; Crowley, George; Mikhail, Mena; Ostrofsky, Dean; Gironda, Zakia; Vaidyanathan, Sandhya; Wadghiri, Youssef Zaim; Liu, Mengling; Kwon, Sophia; Nolan, Anna
PMID: 34354194
ISSN: 2045-2322
CID: 5004272

Food Intake REstriction for Health OUtcome Support and Education (FIREHOUSE): A Randomized Clinical Trial [Meeting Abstract]

Young, I. R.; Lam, R.; Kwon, S.; Crowley, G.; Riggs, J.; Ostrofsky, D.; Nayar, C.; Zeig-Owens, R.; Schwartz, T. M.; Colbeth, H. L.; Mikhail, M.; Veerappan, A.; Pompeii, M.; St-Jules, D. E.; Liu, M.; Prezant, D. J.; Sevick, M. A.; Nolan, A.
ISI:000685468902597
ISSN: 1073-449x
CID: 5519102

Exogenous RAGE Inhibitor Attenuates Particulate Matter Induced Airway Hyperreactivity [Meeting Abstract]

Veerappan, A.; Sunseri, M.; Crowley, G.; Kwon, S.; Young, I. R.; Nolan, A.
ISI:000685468900095
ISSN: 1073-449x
CID: 5519062

Metabolomics at the Intersection of Murine WTC-PM Exposure and High Fat Diet: A Machine Learning Assessment [Meeting Abstract]

Crowley, G.; Caraher, E.; Veerappan, A.; Lam, R.; Haider, S.; Kwon, S.; Liu, M.; Nolan, A.
ISI:000685468904319
ISSN: 1073-449x
CID: 5519112

Increasing Sphingolipid Synthesis Alleviates Airway Hyperreactivity

Heras, Andrea F; Veerappan, Arul; Silver, Randi B; Emala, Charles W; Worgall, Tilla S; Perez-Zoghbi, Jose; Worgall, Stefan
RATIONALE/BACKGROUND:Impaired sphingolipid synthesis is linked genetically to childhood asthma and functionally to airway hyperreactivity. OBJECTIVES/OBJECTIVE:To investigate if sphingolipid synthesis could be a target for asthma therapeutics. METHODS:The effects of GlyH-101 and fenretinide via modulation of de novo sphingolipid synthesis on airway hyperreactivity was evaluated in mice deficient in serine palmitoyl-CoA transferase, the rate limiting enzyme of sphingolipid synthesis. The drugs were also used directly in human airway smooth muscle and epithelial cells to evaluate changes in de novo sphingolipid metabolites and calcium release. RESULTS:GlyH-101 and fenretinide increased sphinganine and dihydroceramides (de novo sphingolipid metabolites) in lung epithelial and airway smooth muscle cells, decrease intracellular calcium concentration in airway smooth muscle cells, and decrease agonist-induced contraction in proximal and peripheral airways. GlyH-101 also decreased airway hyperreactivity in SPT-deficient mice in vivo. CONCLUSIONS:This study identifies the manipulation of sphingolipid synthesis as a novel metabolic therapeutic strategy to alleviate airway hyperreactivity.
PMID: 32706610
ISSN: 1535-4989
CID: 4534362

Food Intake REstriction for Health OUtcome Support and Education (FIREHOUSE) Protocol: A Randomized Clinical Trial

Kwon, Sophia; Riggs, Jessica; Crowley, George; Lam, Rachel; Young, Isabel R; Nayar, Christine; Sunseri, Maria; Mikhail, Mena; Ostrofsky, Dean; Veerappan, Arul; Zeig-Owens, Rachel; Schwartz, Theresa; Colbeth, Hilary; Liu, Mengling; Pompeii, Mary Lou; St-Jules, David; Prezant, David J; Sevick, Mary Ann; Nolan, Anna
Fire Department of New York (FDNY) rescue and recovery workers exposed to World Trade Center (WTC) particulates suffered loss of forced expiratory volume in 1 s (FEV1). Metabolic Syndrome increased the risk of developing WTC-lung injury (WTC-LI). We aim to attenuate the deleterious effects of WTC exposure through a dietary intervention targeting these clinically relevant disease modifiers. We hypothesize that a calorie-restricted Mediterranean dietary intervention will improve metabolic risk, subclinical indicators of cardiopulmonary disease, quality of life, and lung function in firefighters with WTC-LI. To assess our hypothesis, we developed the Food Intake REstriction for Health OUtcome Support and Education (FIREHOUSE), a randomized controlled clinical trial (RCT). Male firefighters with WTC-LI and a BMI > 27 kg/m2 will be included. We will randomize subjects (1:1) to either: (1) Low Calorie Mediterranean (LoCalMed)-an integrative multifactorial, technology-supported approach focused on behavioral modification, nutritional education that will include a self-monitored diet with feedback, physical activity recommendations, and social cognitive theory-based group counseling sessions; or (2) Usual Care. Outcomes include reduction in body mass index (BMI) (primary), improvement in FEV1, fractional exhaled nitric oxide, pulse wave velocity, lipid profiles, targeted metabolic/clinical biomarkers, and quality of life measures (secondary). By implementing a technology-supported LoCalMed diet our FIREHOUSE RCT may help further the treatment of WTC associated pulmonary disease.
PMID: 32916985
ISSN: 1660-4601
CID: 4590272