My role in basic and clinical research has largely derived from my position as Director of the Molecular Biology Core in the Section of Pulmonary Medicine. In that capacity, I have generated and characterized lung-specific overexpressing transgenic and null mutant mice to study in vivo roles and the effect of various cytokines in the pathogenesis of asthma, acute lung injury, pulmonary vascular disease, pulmonary fibrosis and emphysema.
My current research interest is to define the molecular mechanism regulating pulmonary fibrosis and emphysema. Although cigarette smoke (CS) is a common risk factor for the development of these pathologies, the mechanism underlying this divergent tissue response of CS exposure has not been clearly understood. Interestingly, we have found that the TGF-b Tg mice in different genetic backgrounds demonstrated divergent tissue phenotypes of pulmonary fibrosis and emphysema. This observation led to the identification of genetic factors that modulate TGF-b effector function. Through extensive haplotype analysis and mRNA expression arrays, we further determined potential genetic modifiers. More recently, my lab has focused on defining the mechanism of vascular and tissue remodeling associated with dysregulated expression of Chitinase/Chitinase-like proteins(C/CLP). Using expertise in developing genetically modified mice and animal models, I will be able to determine specific pathogenetic mechanism of various lung diseases characterized by inflammation and remodeling that is essential for further development of therapeutic intervention on these diseases.
Selection of optimized lead compounds for preclinical studies for idiopathic pulmonary fibrosis using a novel RNAi-based nanoparticle technology SAMiRNA
Bioneer, a biotech company in Korea, developed Self Assembled Micelle-inhibitory RNA (SAMiRNA) technology as a novel and effective siRNA delivery method. In this project, the effectiveness of this SAMiRNA approach against pulmonary fibrosis will be determined through a variety of in vivo and in vitro evaluations and also using TGF-b transgenic mice developed by our laboratory as an animal model of pulmonary fibrosis. Thus, successful completion of this project will lead to the development of new drug for the effective intervention of pulmonary fibrosis.
Role: Principal Investigator
1 R01 HL115813-01A1 (Lee) 7/1/14 – 6/31/18
NIH / NHLBI $254,707
Chitinase 1 as a Biomarker and Therapeutic Target in Scleroderma Lung Disease
This grant proposes to define the roles and effects of chitinase1 in the pathogenesis of Scleroderma-associated interstitial lung disease. The studies in this project will evaluate the levels of chitinase1 in the blood or tissues of Scleroderma patients and controls to identify chitinase1 as a potential biomarker or a therapeutic target for this disease.
Role: Principal Investigator
1U01 HL 108638-01 (Elias) 8/15/11 – 6/30/15
NIH / NHLBI $396,455
YKL-40 in Idiopathic Pulmonary Fibrosis and Kidney Transplantation
This grant is designed to evaluate circulating YKL-40 as a biomarker for disease progression in IPF and urinary YKL-40 as a predictor of delayed graft function after renal transplantation. These studies will also evaluate the utility of YKL-40 as a therapeutic target in both disorders.
P01 HL114501-01A1 (Choi) 4/1/13 – 3/31/18
NIH / NHLBI $225,000
Distinct and Overlapping Pathways of Fibrosis and Emphysema in Cigarette Smokers
The focus is on the mechanisms that underlie the observation that cigarette smoke exposure and TGF-1 can contribute to the pathogenesis of COPD and IPF. Project 3 is based on evaluations of 10 different inbred murine backgrounds which define genetic modifiers that likely determine if TGF-1 causes fibrosis versus emphysema. These studies will define the expression of these modifiers in COPD and IPF and will define their roles in these biologic responses.
Role: Co-PI, Project 2
5 U01 HL108634 (Zhou/Elias) 9/1/13- 8/31/14 .
MAPGen Knowledge Base (MAPGenKB) and Coordination Center
In this ancillary project, we will measure the levels of YK-40 in patients with atherosclerosis, hypertension, metabolic syndromes and visceral fat accumulation. In addition, we will evaluate the roles of cell cycle regulation and the mitochondrial function in animal model of the diseases.
1 UH2 HL 123876-01 (Chupp/Elias) 7/1/14 – 6/30/19
Preclinical Development of a Novel Anti-YKL-40 Biologic to Treat Severe Asthma
We will complete the pre-clinical development of a humanized monoclonal antibody against the chitinase-like-protein, YKL-40, for the treatment of severe asthma. A companion diagnostic test will also be developed to measure YKL-40 in the serum that is drug-bound or free for monitoring the bioavailability, dosing, and biologic effect. The results will generate a novel therapeutic against a validated mediator of inflammation and remodeling in asthma and will lead to an Investigational New Drug (IND) application following the conclusion of the award.
NIH/ NHLBI 10/1/14 to 9/30/15
R56 HL 119511-01A1 (Bridge Award) (Kang)
NLRX1 and MAVS in cigarette smoke-induced inflammation and alveolar remodeling
The goal of this grant is to define the roles of novel mitochondrial molecules called NLRX1 and MAVS in the development of COPD. In addition, we will explore whether interventions that restore suppressed NLRX1 or modulate this pathway have therapeutic potential in a murine COPD model.