Candidate: My long-term career goal is to develop a successful academic career and become an independently funded physician-scientist focused on the study of innate immunity in idiopathic pulmonary fibrosis (IPF). Under the guidance of my mentor and research advisors, I have received training in laboratory-based assays, in vitro models of IPF, translational medicine, and biostatistics. I have proposed career development activities that will allow me to continue this training, but also develop unique expertise that is distinct from my mentor in the areas of (1) innate immunity and (2) computational biology. Mentors and Environment: I will be mentored by Dr. Erica Herzog, a globally renowned IPF investigator who has studied the immunopathogensis of fibrosis with an extremely impressive track record of successful mentees. My advisors include Dr. Naftali Kaminski, a well-known IPF investigator whose visionary methods in the genomic profiling of fibrotic lung disease have revolutionized the field; Dr. Wajahat Mehal, who has been lauded for his work with mitochondrial DNA (mtDNA) and Toll-Like Receptor 9 (TLR9) in the development of fibrosis; Dr. Min-Jong Kang, an expert in mitochondrial innate immunity in chronic lung disease; and Dr. Anjelica Gonzalez, who has developed novel methods in bioengineering for ex vivo modeling of the fibrotic microenvironment. My department Chair (Dr. Gary Desir) has assured me that at least 75% of my time will be dedicated to my career development, and he and my Section Chief (Dr. Kaminski) have detailed their commitment. Mentored Research Project: The pathogenesis of IPF involves the uncontrolled accumulation of activated myofibroblasts, which arise in response to TGF?1 mediated interactions with the stiff fibrotic lung microenvironment. The innate immune receptor TLR9, which recognizes and responds to mtDNA derived from injured cells, has been shown to have a significant role in mediating this process. We showed that mtDNA is released by TGF?1-stimulated and stiffness-induced normal human lung fibroblasts, where it induces myofibroblast transformation in a manner that phenocopies fibroblasts harvested from the IPF lung. In the clinical setting, mtDNA concentrations are elevated in the plasma of IPF subjects, where it displays a robust association with all-cause mortality in two independent cohorts. Our subsequent studies reveal that mice deficient in TLR9 are protected from fibrosis caused by lung specific overexpression of the bioactive form of the human TGF?1 gene and by repetitive administration of low-dose inhaled bleomycin. While exciting, however, these studies are limited by not having determined whether mtDNA-induced fibroblast activation requires TLR9, whether TLR9?s fibrosis promoting effects are mediated through fibroblasts in vivo, and the nature of the mtDNA-TLR9 relationship in IPF. Because elucidation of these questions might substantially impact our understanding of pulmonary fibrosis, this K08 application proposes a state-of-the-art set of translational studies to test the hypothesis that mtDNA-TLR9 interaction drives fibroblast activation and fibrosis in the adult lung.

Public Health Relevance

While idiopathic pulmonary fibrosis (IPF) is an incurable, fatal disease of an unknown cause, recent studies have shown that the immune system may play a key role in causing this disease. I have previously shown that cells will release their mitochondrial DNA (mtDNA) in response to injury, and this mtDNA can lead to activation of the immune system. Through our cell, mouse, and human studies, I will investigate the ways in which mtDNA interacts with the immune system as one possible cause of IPF, which can lead to exciting new areas of drug development to combat this devastating disease.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Clinical Investigator Award (CIA) (K08)
Project #
Application #
Study Section
NHLBI Mentored Clinical and Basic Science Review Committee (MCBS)
Program Officer
Kalantari, Roya
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Yale University
Internal Medicine/Medicine
Schools of Medicine
New Haven
United States
Zip Code