Biography

(Coming soon.)

Areas of Research

Over the last 26 years, our lab has developed several areas of research related to regulation of gene expression of major components (uPA, uPAR and PAI-1) of the uPA-fibrinolytic system at the posttranscriptional level via mRNA binding proteins. During the early years of my independent research career, my team identified and expressed several mRNA binding proteins (mRNABps) that interact with the cis regulatory elements in a sequence specific manner to regulate uPA, uPAR and PAI-1 expression. We also discovered that the tumor suppressor protein, p53 is a sequence specific mRNABp that interacts with unique 3’UTR sequences of uPA, uPAR and PAI-1 mRNA. The 3’UTR sequence contained information for mRNA destabilization.

Over the past several years, we found that the uPA system contributes to lung injury and alveolar epithelial cell (AEC) programmed cell death; apoptosis, in four different preclinical animal models and in primary AECs isolated from the lungs of patients with IPF and COPD. We further demonstrated that targeting p53 interaction with endogenous uPA, uPAR and PAI-1 mRNA inhibits AEC apoptosis and prevents subsequent development of lung scarring. We also found that the caveolin-1 (Cav1) scaffolding domain peptide (CSP) or its seven amino acid fragment CSP7 (also called LTI-03) inhibits p53 and reverses p53-mediated downstream changes in uPA, uPAR and PAI-1 expression. CSP7 also reversed cigarette smoke or bleomycin (BLM) or silica-induced AEC senescence and apoptosis and prevented development of lung scarring.

We also found that unlike injured AECs, basal expression of p53 in myofibroblasts or fibrotic lung fibroblasts (fLfs) is very low due to low basal Cav1 expression and increased mdm2-mediated degradation of p53 protein. CSP7 directly binds to mdm2 in the absence of Cav1 and inhibits mdm2-mediated degradation of p53. This in turn restores baseline p53 expression and restrains proliferation of fLfs and matrix protein deposition. Therefore, inhibition of p53 in injured AECs by CSP7 inhibits AEC apoptosis and inflammation, while CSP7-mediated reinstatement of p53 expression in fLfs inhibits excess proliferation and deposition of matrix proteins thereby resolving existing lung scarring; pulmonary fibrosis (PF). The peptide is well tolerated, resolves PF in mice with either established BLM- or TGF-β-induced PF, can be nebulized with retention of activity and has the potential for great medical impact.

We were recently granted three patents from the US patent office to treat lung injury and PF. Lastly, we believe LTI-03 will be a new, safe and potentially more effective intervention for patients with IPF or other interstitial lung diseases for which cure is unavailable and for whom alternative drug options that can durably improve outcomes remain limited. This new candidate intervention targets a different cellular signaling pathway than other pharmaceutical approaches. Lung Therapeutics, Inc. (LTI) is currently developing LTI-03 for the treatment of idiopathic pulmonary fibrosis (IPF).

Areas of Major Research Interest and current projects:

COPD, lung fibrosis, lung epithelial biology and airway and alveolar remodeling. Gene expression, posttranscriptional regulation, peptide drug development for COPD and IPF/interstitial lung diseases. Epigenetic control of lung injury and lung fibrosis, drug delivery, pharmacokinetics and toxicology of peptide therapeutics.

Peer-reviewed publications (in chronological order):

Marudamuthu AS, Bhandary, YP, Gopu V, Fan L, Radhakrishnan V., Mackenzie, B, Maier, E, Shetty SK, Nagaraja MR, Gopu, V, Tiwari N, Zhang Y, Watts AB, Williams RO, Criner GJ, Marchetti N, Bolla S, Idell S, and Shetty S (2019) Resolution of Pulmonary Fibrosis by a Caveolin-1-Derived Peptide. Sci Transl Med 11, eaat2848.
Nagaraja MR, Tiwari N, Shetty SK, Marudamuthu AS, Fan L, Ostrom RS, Fu J, Gopu V, Radhakrishnan V, Idell S, and Shetty S (2018) p53 expression in lung fibroblasts is linked to mitigation of fibrotic lung remodeling. Am J Pathol 188: 2207-2222.
Hengsawas SS, Florova G, Komissarov AA, Shetty S, Idell S, Williams RO (2017) Formulation for a Novel Inhaled Peptide Therapeutic for Idiopathic Pulmonary Fibrosis. Drug Dev Ind Pharm. 23:1-54. PMID: 28835128.
Shetty SK, Tiwari N, Marudamuthu AS, Puthusseri B, Bhandary YP, Idell S, Fu J, Levin J, and Shetty S (2017) p53 and microRNA-34a feedback promotes lung epithelial injury and remodeling. Am J Pathol 187:1016-1034. PMID: 28273432.
Puthusseri B, Marudamuthu A, Tiwari N, Fu J, Idell S and Shetty S (2017) Induction of p53 and downstream changes by loss of surfactant protein-C expression in alveolar epithelial cells during lung injury. Am J Physiol Lung Cell Mol Physiol. 312: L783–L796. PMID: 28385810.
Dong C, Li B, Li Z, Shetty S and Fu J. Dasatinib-loaded albumin nanoparticles possess diminished endothelial cell barrier disruption and retain potent anti-leukemia cell activity. Oncotarget 7(31):49699-49709, 2016.
Tiwari N, Marudamuthu AS, Tsukasaki Y, Ikebe M, Fu J, Shetty S. p53- and PAI-1-mediated induction of C-X-C chemokines and CXCR2: Importance in Pulmonary Inflammation due to Cigarette Smoke exposure. Am J Physiol Lung Cell Mol Physiol. 310: L496–L506, 2016.
Marudamuthu AS, Shetty SK, Bhandary YP, Karandashova S, Thompson M, Sathish V, Florova G, Hogan T, Pabelick C, Prakash YS, Idell S and Shetty S. Plasminogen activator inhibitor-1 suppresses pro-fibrotic responses in fibroblasts from fibrotic lungs. J Biol Chem 290(15):9428-9441, 2015.
Marudamuthu AS, Bhandary YP, Shetty SK, Fu J, Sathish V, Prakash YS and Shetty S. Role of the Urokinase-fibrinolytic system in epithelial mesenchymal transition during lung injury. Am J Pathol 185(1)55-68, 2015.
Bhandary YP, Shetty SK, Marudamuthu AS, Fu J, Pinson BM, Levin J and Shetty S. Role of p53-fibrinolytic system cross-talk in the regulation of quartz-induced lung injury. Toxicol Appl Pharmacol 283(2)92-98, 2015.
Bhandary YP, Shetty SK, Marudamuthu AS, Ji H, Boggaram, VB, Neuenschwander PF, Morris GB, Fu J, Idell S and Shetty S. Regulation of alveolar epithelial injury and lung remodeling by p53-mediated changes in urokinase and plasminogen activator inhibitor-1. Am J Pathol 183,131-143, 2013.
Shetty SK, Bhandary YP, Marudamuthu AS, Abernathy D, Veluswamy T, Starcher B, and Shetty S. Regulation of Airway and Alveolar Epithelial Cell Apoptosis by p53 Induced PAI-1 During Cigarette Smoke Exposure Injury. Am J Respir Cell Mol Biol 47:474-483, 2012.
Shetty SK, Marudamuthu AS, Abernathy D, Shetty RS, Shetty P, Fu J, Idell S, Bhandary YP, Ji H, Liu MC, and Shetty S. Regulation of urokinase expression at the posttranscriptional level by lung epithelial cells. Biochemistry 51:205-213, 2012.
Bhandary YP, Shetty SK, Marudamuthu AS, Gyetko MR, Idell S, Gharaee-Kermani M, Shetty RS, Starcher BC, and Shetty S. Regulation of alveolar epithelial cell apoptosis and pulmonary fibrosis by coordinate expression of components of the fibrinolytic system. Am J Physiol Lung Cell Mol Physiol 302:L463-L473, 2012.
Shetty S, Bhandary YP, Shetty SK, Velusamy T, Shetty P, Bdeir K, Gyetko MR, Cines DB, Idell S, Neuenschwander PF, Ruppert C, Guenther A, Abraham E, and Shetty RS. Induction of tissue factor by urokinase in lung epithelial cells and in the lungs. Am J Respir Crit Care Med 181:1355-1366, 2010.
Shetty S, Velusamy T, Shetty RS, Marudamuthu AS, Shetty SK, Florova G, Tucker T, Koenig K, Shetty P, Bhandary YP, and Idell S. Post-transcriptional regulation of plasminogen activator inhibitor type-1 expression in human pleural mesothelial cells. Am J Respir Cell Mol Biol 43:358-367, 2010.
Bhandary YP, Velusamy T, Shetty P, Shetty RS, Idell S, Cines DB, Jain D, Bdeir K, Abraham E, Tsuruta Y, and Shetty S. Post-transcriptional regulation of urokinase-type plasminogen activator receptor expression in lipopolysaccharide-induced acute lung injury. Am J Respir Crit Care Med 179:288-298, 2009.
Shetty P, Velusamy T, Bhandary YP, Shetty RS, Liu MC, and Shetty S. Urokinase expression by tumor suppressor protein p53: a novel role in mRNA turnover. Am J Respir Cell Mol Biol 39:364-372, 2008.
Shetty S, Shetty P, Idell S, Velusamy T, Bhandary YP, and Shetty RS. Regulation of plasminogen activator inhibitor-1 expression by tumor suppressor protein p53. J Biol Chem 283:19570-19580, 2008.
Velusamy T, Shetty P, Bhandary YP, Liu MC, and Shetty S. Posttranscriptional regulation of urokinase receptor expression by heterogeneous nuclear ribonuclear protein C. Biochemistry 47:6508-6517, 2008.
Shetty S, Velusamy T, Idell S, Shetty P, Mazar AP, Bhandary YP, and Shetty RS. Regulation of urokinase receptor expression by p53: novel role in stabilization of uPAR mRNA. Mol Cell Biol 27:5607-5618, 2007.
Shetty S, Gyetko MR, and Mazar AP. Induction of p53 by urokinase in lung epithelial cells. J Biol Chem 280:28133-28141, 2005.
Shetty S, Muniyappa H, Halady PK, and Idell S. Regulation of urokinase receptor expression by phosphoglycerate kinase. Am J Respir Cell Mol Biol 31:100-106, 2004.
Shetty S, Bdeir K, Cines DB, and Idell S. Induction of plasminogen activator inhibitor-1 by urokinase in lung epithelial cells. J Biol Chem 278:18124-18131, 2003.
Shetty S and Idell S. Urokinase induces expression of its own receptor in Beas2B lung epithelial cells. J Biol Chem 276:24549-24556, 2001.
Shetty S, Kumar A, and Idell S. Posttranscriptional regulation of urokinase receptor mRNA: identification of a novel urokinase receptor mRNA binding protein in human mesothelioma cells. Mol Cell Biol 17:1075-1083, 1997.
Shetty S, Kumar A, Johnson AR, Pueblitz S, Holiday D, Raghu G, and Idell S. Differential expression of the urokinase receptor in fibroblasts from normal and fibrotic human lungs. Am J Respir Cell Mol Biol 15:78-87, 1996.