Systemic inflammation and organ damage after cardiopulmonary bypass surgery in pediatric patients – Nigam lab, Seattle Children’s Research Institute

Surgical repair of congenital heart defects requires support of cardiopulmonary bypass (CPB) in which blood is pumped through an artificial circuit at high shear stress to maintain organ perfusion. Pediatric patients have high morbidity and mortality after CPB with unknown mechanism. Exposure to CPB causes dysfunction in the heart, brain, kidneys, lungs, and other organs.

• Uncovered that the CPB-associated systemic inflammation in pediatric patients is primarily driven by monocyte activation. Demonstrated for the first time that the molecular mechanism of shear stress-activated inflammation is via calcium signaling pathways: MEK/ERK/AP-1 and Calcineurin/NFAT. Targeting these pathways by FDA-approved drugs such as FK506 (Tacrolimus) significantly blunted the inflammatory response.
• Elucidated the novel mechanism how CPB-associated inflammation contributes to postoperative organ damage: a subpopulation of activated monocytes infiltrates into tissues and dies by necroptosis. Neutralizing TNFα by Adalimumab-equivalent antibody could prevent this mode of damaging cell death, potentially ameliorating the organ damage.
• Provided the first comprehensive view of global transcriptional changes in the striatum (the region of the brain involved in decision-making, reward cognition and motor functions) after deep hypothermic circulatory arrest, a form of CPB, using a piglet CPB model. Demonstrated strong activation of both inflammatory and apoptotic signaling pathways in the striatum after CPB. NF-kB was identified as an upstream regulator of majority of the upregulated genes, hence a novel target to be tested for beneficial effects on neurologic outcome.
• Published 2 research papers

Defective fatty acid oxidation in alveolar type II cells promotes senescence and lung fibrosis – Mora lab, University of Pittsburgh

• Analyzed metabolomics data from human lung tissues and uncovered that with age, glycolysis increases while lipid metabolism, specifically mitochondrial fatty acid oxidation (FAO), declines. In idiopathic pulmonary fibrosis – the disease which predominantly affects the elderly population, FAO deteriorates specifically in alveolar type II cells as characterized by reduced expression of the key FAO protein CPT1A.
• Demonstrated for the first time that loss of CPT1A function in alveolar epithelial cells caused cellular senescence and expression of profibrotic factors. Pharmacological inhibition of CPT1A promoted the development of lung fibrosis in a mouse model. This provides the basis for therapeutic manipulations of alveolar epithelial cell metabolism as a novel treatment against lung fibrosis.
• Paper under preparation (pending more human data).

Mitochondrial dysfunction in pulmonary arterial hypertension – Mora lab, University of Pittsburgh

• Demonstrated that PINK1 deficiency caused severe mitochondrial dysfunctions in human pulmonary artery endothelial cells (PAECs), making the cells more fragile and susceptible to injuries. This helps to further understand the etiology of pulmonary arterial hypertension.
• Poster presentation at the American Thoracic Society International Conference.

Molecular function of the translocator protein in physiology and pathology – Selvaraj lab, Cornell University

Translocator protein (TSPO) is a highly conserved protein from bacteria to human. Its expression is dysregulated in many different diseases, making it an attractive therapeutic and diagnostic target in human medicine. However, its exact function remains unclear.

• Refuted the 25-year-old dogma that TSPO was not involved in mitochondrial cholesterol import for steroid hormone biosynthesis using knockout mouse model and CRISPR/Cas9 – mediated knockout cell lines. Effects of commonly used TSPO ligands on steroid hormone production were shown to be non-specific and likely off-target effects. (Press release: http://www.jbc.org/content/289/40/27455).
• Demonstrated the true molecular function of TSPO in tetrapyrrole homeostasis at the cellular level; the impact of TSPO loss/gain of function on lipid metabolism, particularly mitochondrial fatty acid oxidation, and neuroinflammation at the whole animal level.
• Published 5 research papers, 3 reviews and 1 commentary.

Metabolomics of a non-obese nonalcoholic fatty liver disease model in mice – Selvaraj lab, Cornell University

• Mice fed high fat, high cholesterol, cholate diet for 3 weeks developed hepatic pathology similar to nonalcoholic fatty liver disease (NAFLD) without changes to body weight. Using lipidomics and metabolomics, demonstrated that mechanisms leading to steatosis and hepatitis in this non-obese NAFLD model were a combination of effects directed by elevated free cholesterol, cholesterol esters and cholic acid, and changes to metabolism of sphingomyelins and phosphatidylcholines. This provides one of the first metabolite reference profiles for interpreting effects of dietary and hepatic cholesterol in human non-obese NAFLD patients.
• Published 1 research paper. Received the NIH metabolomics pilot grant.

Protein-protein interaction and subcellular localization profiles of paraneoplastic Ma antigen family of proteins – Yu lab, National University of Singapore

• Established subcellular localization and protein-protein interaction network of all PNMA proteins. Demonstrated the biological significance of the interaction between PNMA-2 and -4 that inhibited ubiquitination and proteasomal degradation.
• Selected as 2nd best honor thesis project in Department of Pharmacy.

Pharmacodynamic & pharmacokinetic profiles of drug candidates – GlaxoSmithKline, Center for research in cognitive & neurodegenerative disorders, Singapore

• Performed in-vivo (mice & rats) pharmacodynamic assays in different disease models. Assisted in developing new animal models to study blood brain barrier integrity. Performed pharmacokinetic assays using HPLC-MS/MS machine.

Anti-proliferative activity of electrophilic compounds and inhibition of thioredoxin reductase – Chew lab, National University of Singapore

• Systematically tested the anti-proliferative activity of 20 electrophilic compounds and their ability to inhibit thioredoxin reductase in breast and colorectal cancer cell lines.
• Synthesized a novel hit compound with strong anti-cancer activity.
• Published 1 co-authored paper. Selected for oral presentation at the department symposium.