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Determining a role for long noncoding RNAs in smoke-induced

Institution: University of California, Santa Cruz
Investigator(s): Susan Carpenter, Ph.D.
Award Cycle: 2018 (Cycle 27) Grant #: 27IP-0017 Award: $500,000
Subject Area: Pulmonary Disease
Award Type: High Impact Pilot Award
Abstracts

Initial Award Abstract

Chronic obstructive pulmonary disease (COPD) is a debilitating inflammatory lung disease associated with tobacco smoking and the third leading cause of death worldwide. COPD is made up of a number of clinical features including airway inflammation (chronic bronchitis) in addition to destruction of lung tissue (emphysema). The processes involved in leading to these clinical manifestations are poorly understood. We know that inflammation associated with cigarette smoke (CS) is a contributing factor, however little is known about what drives the chronic inflammation observed in COPD. Current treatments fail to inhibit this chronic inflammation activated by CS exposure. Thus, there is a desperate need for new avenues of investigation aimed at identifying novel regulators of smoke-induced inflammation.

We are interested in studying RNA genes and determining their role in controlling inflammation. From RNA-sequencing studies we now know that less than 3% of the human genome codes for protein, yet over 85% is actively transcribed. Why so much RNA is produced and whether it is all biologically relevant remains a fundamental unsolved problem. Long noncoding RNAs (lncRNAs), defined as transcripts greater than 200 nucleotides that do not encode proteins, represent the largest group of genes transcribed from the genome. LncRNAs have emerged as key regulators of biological processes and we have discovered the first case of a lncRNA that functions to regulate inflammation in critical immune cells called macrophages. Specifically, we identified lincRNA-Cox2, as one of the top genes turned on following inflammation, which functions to regulate critical genes within inflammatory pathways.

The aim of our research is to better understand the basic mechanisms involved in controlling inflammation within chronic obstructive pulmonary disease. This project is a pilot study to test our hypothesis that lncRNAs function within the immune system to control inflammation. We are taking two approaches to test our hypothesis; one is a high throughput approach to study all lncRNAs and identify those involved in controlling inflammation and the second is a focused approach to study lincRNA-Cox2 in animal models to determine if it is involved in COPD disease progression. Completing this project will accelerate our long-term goal of identifying new targets for therapeutic intervention for COPD.