Asthma; Immunity, Cellular; Macrophage Activation; Neoplasms; Angiogenesis Inhibitors; MicroRNAs; Vascular Endothelial Growth Factor A
My research is focused on understanding the molecular basis of a variety of lung disease ranging from asthma to lung cancer. I study the role of a recently discovered group of genes called non-coding RNAs (ncRNAs). These molecules are expressed in the cells, but rather than coding a specific protein, target and modify the expression of other RNAs including messenger RNAs (mRNAs).
In our workflow we first measure the levels of coding and non-coding RNAs in human samples and animal models to identify changes in ncRNAs and candidate target genes that are unique to a specific lung pathology. We then analyze the relationship between these regulatory elements through various bioinformatic and biochemical methods. Finally, we directly investigate the role of these ncRNAs and their targets by modulating their expression in disease models and testing their effects on specific pathogenic mechanisms.
One of our main research interests in recent years has been the role of ncRNAs in the lung endothelium. We are trying to answer questions such as how and why vascular cells become inflamed in diseases like asthma and how activation of these cells permits the propagation of cancerous cells in the lung. In our investigations we found that the levels of a specific small ncRNA; microRNA-1 ( miR-1), closely corresponds with the severity of vascular involvement in inflammation and cancer models. Using various molecular tools we identified a genuine target of miR-1 in lung endothelial cells and have so far shown that modulation of miR-1 or its target in asthma models inhibits the lung inflammatory response. We are currently examining the role of miR-1 in lung cancer. Recently we have expanded the scope our work and are currently examining the effect of miR-1 and a number of other ncRNAs in other lung diseases such as emphysema and lung injury.
Extensive Research Description
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.
We have found that miR-1 is specifically down-regulated by VEGF through VEGF receptor- 2 in the lung endothelium and mediates the angiogenic and inflammatory effects of VEGF. We have shown that miR-1 selectively controls the proliferative pathways downstream from VEGF and directly down-regulates the expression of Myeloproliferative Leukemia Oncogene (Mpl) mRNA by recruiting it to RISC (RNA Induced Silencing Complex). We have also found that, through regulation of Mpl, miR-1 controls the expression of adhesion molecules, namely P-selectin, on the lung endothelium, recruitment of Tcells, and severity of lung Th2 inflammation. We have developed vector-based and transgenic models for cell-specific expression of miRNAs and their targets in the lung. Using these tools, we have shown that miR-1/Mpl axis controls VEGF-mediated effects in lung angiogenesis and Th2 inflammation. These findings are not limited to animal models, and miR-1 is also regulated by VEGF and controls Mpl gene in human endothelial cells.
We have developed two experimental models for studying the role of miRNAs in tumor progression and metastasis and are currently working on the molecular mechanism of miR-1 down-regulation in the endothelium. Recently we have expanded our studies to the other lung pathologies where VEGF plays a major role. In our collaboration with Dr. Patty Lee we are investigating the role of VEGF and VEGF-induced miRNAs in lung injury and COPD.
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. We have also started a collaboration with the 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. Through this collaboration we collect samples from resected lung tumors for their miRNA content, and analyze the correlation of miRNA expression with lung tumor progression.
- The role of miR-1 in mediating the VEGF-mediated angiogeneis and vascular activation in the lung
-The role of VEGF/miR-1 axis in Th2 adaptive Immunity
-The effect of TLR4-related non-coding RNAs on VEGF signaling in the lung
-The role of microRNA in the Activation of Macrophages
- VEGF controls lung Th2 inflammation via the miR-1-Mpl (myeloproliferative leukemia virus oncogene)-P-selectin axis. Takyar S, Vasavada H, Zhang JG, Ahangari F, Lee CG, Niu N, Liu Q, Cohn L, Elias JA. 'VEGF Controls Lung Th2 Inflammation Via the Mir-1-Mpl (Myeloproliferative Leukemia Virus Oncogene)-P-Selectin Axis', Journal of Eexperimental Medicine, 210 (2013), 1993-2010.
- RIG-like helicase innate immunity inhibits vascular endothelial growth factor tissue responses via a type I IFN-dependent mechanism. Ma B, Dela Cruz CS, Hartl D, Kang MJ, 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. 2011 May 15;183(10):1322-35
- mRNA helicase activity of the ribosome. Takyar S, Hickerson RP, Noller HF. mRNA helicase activity of the ribosome, Cell, 2005, 120:49-58?.
- Role of chitin and chitinase/chitinase-like proteins in inflammation,tissue remodeling, and injury. Lee CG, Da Silva CA, Dela Cruz CS, Ahangari F, Ma B, Kang MJ, He CH, Takyar S, Elias JA. Role of chitin and chitinase/chitinase-like proteins in inflammation,tissue remodeling, and injury. Annu Rev Physiol. 2011 Mar 17;73:479-501.
- Vitamin B12 and hepatitis C: molecular biology and human pathology. Takyar S and Lott WB, Tuppen J, Crawford DHG, Harrison M, Sloots TP, Gowans EJ. Vitamin B12 and hepatitis C: molecular biology and human pathology, Proceedings of the National Academy of Sciences (PNAS), 2001, 98:4916-4921
- Vitamin B12 stalls the 80 S ribosomal complex on the hepatitis C internal ribosome entry site. Takyar S, Gowans EJ, Lott WB. Vitamin B12 stalls the 80 S ribosomal complex on the hepatitis C internal ribosome entry site, Journal of Molecular Biology, 2002, 319:1-8.
- Specific detection of minus-strand hepatitis C virus RNA by reverse-transcription polymerase chain reaction on PolyA(+)-purified RNA. Takyar S, Li DS, Wang YH, Trowbridge R, Gowans EJ. Specific detection of minus strand hepatitis C virus RNA by RT-PCR on a polyA purified RNA, Hepatology, 2000, 32:382-387.