The Division of Pulmonary, Critical Care, and Sleep Medicine is involved in many clinical and translational research projects. Active areas of research include clinical trials of biologics in obstructive lung disease, multi-omics in COPD and IPF, and observational studies in critical care.
Gene expression signatures of extrapulmonary sarcoidosis
Previous research has identified selected genes, particularly from a part of the cell machinery called the mitochondria, that have been associated with sarcoidosis affecting many organs. However, there have not been any studies that investigate which genes may be related to sarcoidosis affecting many organs across the entire human genome using state-of-the-art RNA sequencing technology. Our project will compare the expression of genes in the blood of patients with sarcoidosis in many organs to patients with sarcoidosis only in the lungs to identify which genes are different between the two groups.
Genetic and genomic resilience to COPD
Chronic obstructive pulmonary disease is an important cause of respiratory morbidity and mortality. While there are many strong risk factors for COPD (e.g., age and cigarette smoking), there is considerable variability in disease that is unexplained by these factors. There has been significant progress in our understanding of the genetic and biologic bases of COPD, which has led to improved quantification of individual risk for disease. Yet, despite being at considerable levels of risk, some individuals do not develop disease. Research on resilience to COPD remains almost entirely unexplored, despite the considerable public health ramifications of identifying factors that ameliorate risk. Resilience, in the context of genetics and biology, represents the capacity to withstand the risk of disease. As the reliability of risk-prediction in COPD increases, so too does the prospect of investigating resilience to COPD. Resilience, in the context of genetics and biology, represents the capacity to withstand the risk of disease. As the reliability of risk-prediction in COPD increases, so too does the prospect of investigating resilience to COPD. Understanding how some individuals with high genetic risk and/or high burden of environmental exposure (e.g., heavy cigarette smokers with normal lung function) avoid developing COPD may uncover novel opportunities to prevent development, intervene at early stages, and treat established and advanced disease. One approach to identifying factors contributing to resilience has been successfully demonstrated in non-pulmonary diseases, including schizophrenia and Alzheimer’s disease, in the form of validated polygenic resilience scores. We hypothesize that polygenic and transcriptional elements contribute to resilience to COPD, and identification of resilient phenotypes will significantly advance our understanding of observed heterogeneity in the genomic and environmental risk of COPD, which can be used to identify novel phenotypes of resilience.
Understanding variability in MUC5B expression in idiopathic pulmonary fibrosis
Idiopathic pulmonary fibrosis is a progressive and often fatal lung disease characterized by destruction of lung parenchyma and accumulation of dense fibrotic tissue. There are a number of genetic factors that have been associated with the risk of development of IPF. The mucin 5B promoter variant rs35705950 has repeatedly been shown to be the largest contributor to the genetic susceptibility of IPF. The putative mechanism by which the variant increases risk of disease is thought to be its role as an expression quantitative trait locus, such that the presence of the MUC5B promoter variant leads to increased expression of MUC5B. However, increased MUC5B expression has been demonstrated in IPF independent of the MUC5B promoter variant. Therefore, there is substantial variability in MUC5B expression in IPF that remains unexplained. Previous studies have used lung tissue gene-expression data to identify distinct endotypes of IPF. One such endeavor identified an endotype of IPF, enriched for cilium-associated genes, which was found to have higher expression of MUC5B. While several other transcriptomic characteristics were associated with the cilium endotype of IPF, the association of the MUC5B promoter variant with the endotype and any differential effects of the variant as an eQTL between endotypes have not been investigated. Given the large observed effect of the MUC5B promoter variant on the genetic risk of IPF, accounting for approximately 30% of the risk of developing IPF, further insight into its role as an eQTL may advance our understanding of the mechanism of the variant in the pathogenesis of IPF. Our project will test the hypotheses that (1) the MUC5B promoter variant is an endotype-dependent eQTL and that (2) there are other genetic variants and gene regulatory elements associated with the eQTL effect on MUC5B.