Y. Michael Shim, MD (left) and Ani Manichaikul, PhD
Y. Michael Shim, MD, a professor of medicine in the Division of Pulmonary and Critical Care Medicine and Ani Manichaikul, PhD, an associate professor in the Department of Public Health Sciences were awarded a $3 million NIH grant to study how sexual dimorphism impacts risk for developing emphysema.
Chronic Obstructive Pulmonary Disease (COPD) is a leading chronic disease worldwide, causing significant healthcare utilization, morbidity, and mortality. A diagnosis of COPD includes a heterogeneous collection of lung diseases. This proposal will focus on one form of COPD, emphysema. Past studies suggest that sex may significantly impact emphysema severity. However, we do not have a clear mechanistic understanding of how sexual dimorphism drives smokers’ lung tissue injury toward or award from emphysema. Our studies identified a gene module that highly correlated with emphysematous tissue remodeling related to sex differences. These Green module genes were significantly expressed in monocyte lineage cells and correlated with sex differences in the lung tissue single-cell RNA sequencing. We also collaborated with the Multi-Ethnic Study of Atherosclerosis (MESA) and concluded that emphysema severity in 1,346 subjects’ chest CT significantly differed between male vs. female smokers. These studies led us to hypothesize that sex differences alter the monocyte clusters enriched with the Green module genes while causing emphysema.
In this grant, we will determine the role of monocyte-lineage cells on the risk of developing emphysema using a murine model, human lung tissue scRNA-seq, and 1800 patient transcriptomics from MESA cohorts. Emphysema is mainly resistant to all available therapies except lung volume reduction strategy and lung transplant. To date, little is known about the functions of monocytes at the level of single cells in the lungs undergoing emphysematous damage. Therefore, our proposal can provide critical biomolecular information between females and males to assess the risk, identify the dysregulated processes, and help develop strategies to mitigate and treat emphysematous COPD tailored by sexual dimorphism and monocyte biology.
This study will be primarily performed at the University of Virginia School of Medicine by Y. Michael Shim, MD and Ani Manichaikul, PhD. They will collaborate with 3 other institutes: Columbia University’s Graham Barr, MD, MESA Lung PI; Duke University’s Youngmei Liu, PhD, MESA Genetics PI; and Harvard University’s Dawn DeMeo, MD.