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Shervin Takyar, MD, PhD

Associate Professor
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Associate Professor

Biography

I did my PhD in microbiology and molecular biology in The University of Queensland, Australia. During my PhD I worked and published on a variety of projects including developing a new lentiviral vector based on JDV (Jembrana Disease Virus), translational regulation in HCV by small RNA-binding molecules and the viral core protein, and RNA-protein interactions in positive strand RNA viruses. During this time I was also involved in cloning the Australian isolate of HCV with Dr Eric Gowans. My findings in these projects were published in a variety of journal including PNAS, Hepatology, and Journal of Molecular Biology.My next stop was a postdoctoral fellowship with Prof. Harry Noller at the RNA Center in UCSC where I delved deeper into the RNA world and studied the helicase activity of the ribosome during translation. Our work was well received and published in Cell.

I started my Internal Medicine residency at the State University of New York (SUNY) at Buffalo in 2003. During the last year of my residency I took part in a research project led by Dr Sands on the role of TIMP-1 in reactive airway disease. Our work was published in Clinical Immunology. I was then recruited to the Pulmonary Critical Care Fellowship at Yale in 2007, and worked with Dr J Elias to set up a platform for analyzing the role of microRNAs in the lung disease using the transgenic models that have been developed in his lab. I started this work on an inducible, lung-specific, VEGF transgenic model and within the first year of the project found a microRNA that was regulated by VEGF and mediated the effects of this cytokine in the lung. Based on these findings we filed a patent on the diagnostic and therapeutic use of miR-1 in lung disease. I received a K99/R00 award in the third year of my clinical fellowship for my work on this project. I was directly recruited as a tenure-track Assistant Professor in the Yale Pulmonary, Critical Care and Sleep Medicine Section at the end of my fellowship.

I started the R00 phase of my grant in 2014. I established my lab in the Pulmonary and Critical Care Section at Yale and was given a secondary appointment in the Department of Molecular Biophysics and Biochemistry. Focusing on the role of endothelial gene regulation in injury, I collaborated with Dr. P Lee a Yale to show that VEGF is a part of a TLR4-driven protective pathway in the lung endothelium. We showed the significance of this pathway in a variety of endothelial-specific models and published the results in FASEB journal in 2015.

In the next phase, we developed vector-based and transgenic models for endothelial-cell-specific miRNA expression and showed that miR-1 effects on inflammation and remodeling are due to its specific role in the lung endothelium. I started a collaboration with Yale Thoracic Interventional and Yale Thoracic Oncology programs on lung cancer and showed that miR-1 is a predictor of lung cancer survival and is regulated in tumor endothelial cells. As a part of this work we also set up several lung cancer models in the lab, including the KRAS mutant/P53 knockout mouse model I was awarded the American Lung Association Cancer Discovery Award in 2013, presented my findings at ATS in 2014, 2015, and 2016 and published a manuscript describing these results in the American Journal of Respiratory and Critical Care Medicine (AJRCCM) in 2017.

I have followed my molecular studies on miR-1 in several directions. Our studies on the role of miR-1 in tumor endothelium has led to the identification of a novel non-templated addition (NTA) enzymatic pathway. We also found that PI3 kinase/Akt pathway controls miR-1 levels in the endothelium. We presented these findings at the Keystone symposium on “MicroRNAs and Noncoding RNAs,” at the “Lung Development, Injury and Repair” Gordon Research Conference in 2016, at the ATS in 2016, 2017, and 2018. We have continued our studies on the role of miR-1 in the tumor stroma and found that it is regulated in the cancerization field. The preliminary results from these studies were presented at ATS 2018 and 2019.

Following the specific role of miR-1 in the endothelium, we used our vascular specific miRNA expression models to probe the specific roles of endothelial miR-1 in airway inflammation. We also developed an Argonaute 2 cross-linking and immunoprecipitation (Ago-CLIP) method to identify novel miR-1 targets through miRISC analysis. Using these two methods we showed that isolated overexpression of miR-1 in the lung endothelium significantly decreases the severity of airway inflammation and mediates this mechanism through downregulation of eosinophil trafficking genes. Also, through our collaboration with Yale Center for Asthma and Airway Disease (YCAAD), and the Ear Nose Throat Department at Yale, we showed the significance of this miRNA-regulated gene network in human asthma and chronic rhinosinusitis. These findings were published in Journal of Allergy and Clinical Immunology (JACI) in 2020.

Since starting my tenure track position in 2010 I have been awarded the AAP (American Association of Physicians) Junior Investigator Award, ALA Lung Cancer Discovery Award, NIH/NIAID R56 award , ATS R to R award, and a DOD Lung Cancer Idea Development award. We have published our work on asthma and Th2 inflammation in Journal of Experimental Medicine, and Journal of Allergy and Clinical Immunology, our work on non-small cell lung caner tumor endothelium and cancer progression in the American journal of Respiratory and Critical Care Medicine, and our work on the role of endothelium in lung injury in FASEB journal. I have recruited and worked with five postdoctoral fellows, four Associate Research Scientists, and four students over the last seven years. My research currently focuses on the role of vascular non-coding RNAs in cancer, lung injury and airway inflammation.

Appointments

Education & Training

Fellow
Yale University School of Medicine (2010)
Resident
State University of New York - Buffalo (2006)
Fellow
University of California at San Cruz (2003)
PhD
University of Queensland (2002)
PG1
University of Queensland (2001)
MD
Iran University of Medical Sciences (1995)

Research

Overview

The overall goal of my research program is to determine the role of non-coding RNAs in the lung pathologies. My background is in basic molecular biology with a focus on RNA biochemistry and structural biology. We have established the basic experimental tools necessary for the identification and modulation of expression of non-coding RNAs in various cellular compartments of the lung.


Our projects are focused in three major areas:

1. The Role of Endothelial Non-coding RNAS in Lung Inflammation and Cancer

We have shown that miR-1 regulation plays a critical role in determining the endothelial response in lung inflammation and tumor progression. We have also shown that miR-1 targets Mpl in the lung endothelium and modulates the expression of adhesion molecules and recruitment of inflammatory cells into the lung. We have developed an endothelial-specific miR-1 expression lentiviral vector and an inducible endothelial-specific miR-1 transgenic mouse, validated the efficiency and specificity of these models and used them in studies on type 2 inflammation and NSCLC tumor progression and angiogenesis. We have found that endothelial miR-1 also plays a protective role in the lung and modulates “angiocrine signaling” between endothelium and epithelial compartments. Our publications in this area include:

  • I.Takyar S, Vasavada H, Zhang JG, Ahangari F, Niu N, Liu Q, Lee CG, Cohn L, Elias JA. VEGF controls lung Th2 inflammation via the miR-1-Mpl (myeloproliferative leukemia virus oncogene)-P-selectin axis. J Exp Med 2013; 210: 1993-2010. PMID:24043765
  • II.Haslip M, Jin L, Siegel I, Takyar S. Endothelial MicroRNA-1 Protects Against Lung Hyperoxic Injury and Downregulates Ang2 Expression, B57. Gene Regulation: miRNAs and epigenetics, American Thoracic Society; May 1, 2015, A3487-A3487
  • Korde, A., Jin, L., Zhang, J. G., Ramaswamy, A., Hu, B., Kolahian, S., Juan Guardela, B., Herazo-Maya, J., Siegfried, J. M., Stabile, L., Pisani, M. A., Herbst, R. S., Kaminski, N., Elias, J. A., Puchalski, J. T. & Takyar, S.. Lung Endothelial MicroRNA-1 Regulates Tumor Growth and Angiogenesis. Am J Respir Crit Care Med, 2017 Dec 1;196(11):1443-1455. PMID:28853613; PMCID: PMC5736970
  • Korde A, Ahangari F, Haslip M, Zhang X, Liu Q, Cohn L, Gomez JL, Chupp G, Pober JS, Gonzalez A, Takyar S. An endothelial microRNA-1-regulated network controls eosinophil trafficking in asthma and chronic rhinosinusitis. The Journal of Allergy and Clinical Immunology 2020, 145:550-562.

2. The Role of Endothelium and VEGF in Lung Injury and Repair

We have studied the role of VEGF in three different contexts. (a) We studied the interaction of VEGF signaling and endothelial TLR4 in lung injury. We constructed vascular-specific lentiviral vectors and transgenic models to specifically manipulate TLR4 expression in the lung endothelium and found that endothelial TLR4 is required and sufficient for VEGF-mediated protection. A manuscript based on these findings was published in FASEB. (b) The role of RIG-like helicase (RLH): we found that processing of viral RNA mimics by RLH induces an interferon response in the lung and inhibits VEGF-induced angiogenesis. (c) Effect of VEGF on miRNA expression: we found that VEGF overexpression in the lung modulates the levels of 6 different microRNAs. I then showed that microRNA-1 downregulation occurs specifically in the lung endothelium and plays a critical role in VEGF-mediated angiogenesis. Our publications in this area include:

  • Takyar S, Ahangari F, Lee CG, Elias JA. MicroRNA(MiR)-1 Regulates VEGF-induced Angiogenic Responses In The Lung By Inhibiting The Myeloproliferative Leukemia Virus Oncogene ( MPL). A59 Epigenetic of lung development and disease: American Thoracic Society; 2010. p. A2040-A2040
  • Lee CG, Ma B, Takyar S, Ahangari F, Delacruz C, He CH, Elias JA. Studies of vascular endothelial growth factor in asthma and chronic obstructive pulmonary disease. Proc Am Thorac Soc 2011; 8: 512-515. PMID:22052929; PMCID:PMC3359071
  • Ma B, Dela Cruz CS, Hartl D, Kang M-J, Takyar S, Homer RJ, Lee CG, Elias JA. RIG-like Helicase Innate Immunity Inhibits Vascular Endothelial Growth Factor Tissue Responses via a Type I IFN–dependent Mechanism. Am J Respir Crit Care Med 2012; 183: 1322-1335. PMC3114061
  • Takyar S, Zhang Y, Haslip M, Jin L, Shan P, Zhang X, Lee PJ. An endothelial TLR4-VEGFR2 pathway mediates lung protection against oxidant-induced injury. FASEB 2016; 30(3):1317-27. PMID:26655705; PMCID:PMC4750407

3. The Role of Lung Cellular Repair Pathways in Asthma

We have worked in two areas in severe asthma. (a) Tissue Inhibitor of Metalloprotease-1 (TIMP-1) / Matrix Metalloprotease Proteins (MMP) pathway. We examined the role of proteases and their inhibitors in the development of Th2 inflammation and remodeling of the lung. I studied the pattern of gene expression in a TIMP-1 knockout mouse in Dr MF Sands’ lab. We showed that asthma phenotypes are accentuated in TIMP-1 knockout mouse and through quantitative methods showed that TIMP-1 has a critical role in inhibiting Th2-mediated inflammation and remodeling (b) Chitinase pathway: We studies the role of Chitinase 3 like 1 (Chi3L1) in obesity and asthma. We found that chitinases modulate both adipose tissue accumulation and airway hyperreactivity through regulation of Sirtuins. Our publications in this area include:

  • Sands MF, Ohtake PJ, Mahajan SD, Takyar S, Aalinkeel R, Fang YV, Blume JW, Mullan BA, Sykes DE, Lachina S, Knight PR, Schwartz SA. Tissue inhibitor of metalloproteinase-1 modulates allergic lung inflammation in murine asthma. Clin Immunol 2009; 130: 186-198. PMID:18955015; PMCID:PMC2676334
  • Ahangari F, Sood A, Ma B, Takyar S, Schuyler M, Qualls C, Dela Cruz CS, Chupp GL, Lee CG, Elias JA. Chitinase 3-like-1 regulates both visceral fat accumulation and asthma-like Th2 inflammation. Am J Respir Crit Care Med 2015; 191: 746-757. PMID:25629580; PMCID:PMC4407482


We have followed my molecular studies on miR-1 in several directions. Our studies on the role of miR-1 in tumor endothelium has led to the identification of a novel non-templated addition (NTA) enzymatic pathway. We also found that PI3 kinase/Akt pathway controls miR-1 levels in the endothelium. We presented these findings at the Keystone symposium on “MicroRNAs and Noncoding RNAs,” at the “Lung Development, Injury and Repair” Gordon Research Conference in 2016, at the ATS in 2016, 2017, and 2018. We have continued our studies on the role of miR-1 in the tumor stroma and found that it is regulated in the cancerization field. The preliminary results from these studies were presented at ATS 2018 and 2019.

Following the specific role of miR-1 in the endothelium, we used our vascular specific miRNA expression models to probe the specific roles of endothelial miR-1 in airway inflammation. We also developed an Argonaute 2 cross-linking and immunoprecipitation (Ago-CLIP) method to identify novel miR-1 targets through miRISC analysis. Using these two methods we showed that isolated overexpression of miR-1 in the lung endothelium significantly decreases the severity of airway inflammation and mediates this mechanism through downregulation of eosinophil trafficking genes. Also, through our collaboration with Yale Center for Asthma and Airway Disease (YCAAD), and the Ear Nose Throat Department at Yale, we showed the significance of this miRNA-regulated gene network in human asthma and chronic rhinosinusitis. These findings were published in Journal of Allergy and Clinical Immunology (JACI) in 2020.

We are currently pursuing a project on the protective role of miR-1 pathway in lung injury. We have shown that overexpression of miR-1 in the human and murine lung endothelium protects the lung against injury. These are recent observations in multiple ARDS murine models and human ex-vivo lung culture, and strongly suggest that miR-1 would be an effective treatment for SARS-CoV2-induced ARDS.

We collaborate with J.Steitz, Sterling Professor of Molecular Biophysics and Biochemistry and HHMI (Howard Hughes Medical Institute) at Yale on the molecular aspects of our projects, with Dr D. Boffa, Dr J. Puchalski and Dr M. Pisani at Thoracic Oncology Program (TOP), Thorciac Interventional Program, and Pulmonary and Critical Care section respectively, and with Dr Chupp and Dr Gomez at Yale Center for Asthma and Airway disease.

Medical Subject Headings (MeSH)

Angiogenesis Inhibitors; Asthma; Immunity, Cellular; Macrophage Activation; MicroRNAs; Neoplasms; Respiratory Distress Syndrome; Vascular Endothelial Growth Factor A

Research at a Glance

Yale Co-Authors

Frequent collaborators of Shervin Takyar's published research.

Publications

2020

2017

2015

2013

2011

2009

2005

2002

Academic Achievements & Community Involvement

  • activity

    FASEB

  • activity

    European Respiratory Journal

  • activity

    American Journal of Physiology / Lung Cellular and Molecular Physiology

  • activity

    American Journal of Respiratory and Critical Care Medicine

  • activity

    Journal of Cell Biology

Clinical Care

Overview

Seyedtaghi “Shervin” Takyar, MD, PhD, is a Yale Medicine pulmonologist who treats a wide variety of respiratory illnesses.

“I like my job because it involves the whole gamut of medicine,” says Dr. Takyar, “from the simple dry cough of a sinus infection to the most complex types of shock in the intensive care unit that demand the highest level of decision making and sophisticated technology.”

Dr. Taykar’s outpatient clinical focus is chronic obstructive pulmonary disease (COPD), which is the third leading cause of death worldwide and can also lead to lung cancer.

“Because I treat a wide range of diseases, I see how paying attention to simple issues, such as a cough, or indoor pollution, can prevent significant complications down the road,” says Dr. Taykar.

An associate professor of medicine and molecular biophysics and biochemistry at Yale University, Dr. Takyar, was awarded the American Association of Physicians Junior Investigator Award. He has spoken across the country and internationally about his research on ribonucleic acid (RNAs), inflammation, lung injury, and lung cancer.

Clinical Specialties

Internal Medicine; Pulmonology & Sleep Medicine; Pulmonary Critical Care

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