Shervin Takyar, MD, PhD

The overall goal of my research program is to determine the role of endothelial gene regulation in lung pathologies with an emphasis on cancer. My background is in basic molecular biology and RNA biochemistry. Through my PhD and postdoctoral training, I took part in a wide variety of molecular investigations, from cloning and optimization of gene therapy vectors to mechanistic aspects of hepatitis C virus propagation, and finally the structural basis of ribosomal translation. During my residency and clinical fellowship, I became interested in the mechanisms of lung inflammation. However, I chose to focus on the less explored role of endothelium in the inflammatory cascade. These investigations led to my work on VEGF-mediated microRNA regulation and angiogenic activation. Together with my group at Yale, I devised models and methods to specifically probe the endothelial miRNAs. At the same time, I started collaborative projects to investigate the translational aspects of these regulations in lung cancer patients.

We are now exploring the modes of non-coding RNA regulation in the lung with a specific focus on smoking and lung adenocarcinoma. In our miRNA studies we are dissecting the molecular machinery that tailors the prevalence of miRNAs to the activation status of the endothelial cells.

Our projects are focused in three major areas:

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

We investigated the role of endothelial-specific miR-1 in lung inflammation and lung cancer. We developed endothelial-specific miRNA expression vectors and transgenic mouse models and using these tools showed that miR-1 targets Mpl in the lung endothelium, modulates the expression of adhesion molecules, and controls the recruitment of inflammatory cells. In our translational work we investigated the activation status of this pathway in asthma and lung adenocarcinoma (LUAD) patients. We are now studying the molecular mechanisms of miRNA biogenesis and degradation with a specific focus on the cancerization process in the lung and the effects of cigarette smoke on the endothelium. Our publications in this area include:

• 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. PMCID: PMC3782056.
• 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. 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. J Allergy Clin Immunol. 2020 Feb;145(2):550-562. PMCID: PMC8440091.
• Korde A, Ramaswamy A, Anderson S, Jin L, Zhang JG, Hu B, Velasco WV, Diao L, Wang J, Pisani MA, Sauler M, Boffa DJ, Puchalski JT, Yan X, Moghaddam SJ, Takyar SS. Cigarette smoke induces angiogenic activation in the cancer field through dysregulation of an endothelial microRNA. Commun Biol. 2025 Mar 28;8(1):511. PMCID: PMC11953391.

2. The Role of Endothelium in Lung Injury and Repair

We studied the role of endothelial signaling in three different contexts. (a) Using size-selective microarrays and stem-loop Taqman probes we found that VEGF regulates 6 specific mature miRNAs in the lung. We then defined the endothelia-specific VEGF-regulated miRNAs and showed their role in angiogenesis. (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) In collaboration with Dr Patty Lee we studied the interaction of VEGF signaling and endothelial TLR4 in lung injury. Using inducible in vivo models we specifically manipulated TLR4 expression in the lung endothelium and found that endothelial TLR4 is required and sufficient for VEGF-mediated protection. (d) We studied the specific contribution of endothelial VEGF and VEGFR2 to permeability and cell death through downregulation of miR-1. Using endothelial-specific vectors, transgenic models, comparative sequencing, and RISC analysis we defined the targets of the VEGF-miR-1 axis in the injured endothelium.

• 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.
• 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. PMCID: 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. PMCID: PMC4750407.
• Korde A, Haslip M, Pednekar P, Khan A, Chioccioli M, Mehta S, Lopez-Giraldez F, Bermejo S, Rojas M, Dela Cruz C, Matthay MA, Pober JS, Pierce RW, Takyar S. MicroRNA-1 protects the endothelium in acute lung injury. JCI Insight. 2023 Sep 22;8(18):e164816. PMCID: PMC10561733.

3. The Role of Lung Cellular Repair Pathways in Asthma

Apart from our specific investigations of the role of VEGF-miR-1 axis in type 2 inflammation, we have studied two other aspects of severe asthma. (a) the role of 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 type 2 inflammation and remodeling of the lung. I focused on the patterns of gene expression in TIMP-1 knockout mouse in Dr MF Sands’ lab and found that TIMP-1 plays a critical role in inhibiting lung inflammation and remodeling. (b) Chitinase pathway: We studied 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