Post-Transcriptional Gene Regulation of Inflammatory Genes in Steroid-Resistant COPD
Abstract
Topic Area: Respiratory Health. COPD (chronic obstructive pulmonary disease) is a terrible disease in which the lungs are permanently damaged, and it is usually associated with long-standing cigarette smoking. No effective treatments or drugs exist. These are the folks whom you see at Walmart and other stores hooked up to oxygen tanks. They can only take a few steps before they have to sit down, if they can walk at all. They will be on these oxygen tanks for the rest of their lives. A diagnosis of COPD is essentially a slow death sentence. It adversely affects our Veteran patients since increased numbers of them have COPD. Steroids, such as prednisone, are last resort drugs prescribed to treat COPD patients, but taking steroids long term has bad side effects and they don’t really work that well in many COPD patients. However, there is a subpopulation of COPD patients who do not even respond to steroids, so-called steroid-unresponsive COPD; these patients do far worse than other COPD patients. A recent publication by the Christensen group identified the cytokine IL-17A as playing an important role in steroid-unresponsive COPD. Cytokines are substances, such as growth factors, which are made by immune system cells that influence other cells and tissues in the body. IL-17A is a double-edged sword: it can help the body to heal, but in situations such as COPD it also drives lung inflammation, resulting in permanent damage, as seen in steroid-unresponsive COPD. Interestingly, Christensen’s group did not identify the source of IL-17A in their publication. For their experiments, they obtained lung specimens from bronchoscopy, a procedure in which the patient has to be knocked out and a tube inserted into their lungs to sample the cells, called airway brushings. Hence this is a very impractical way to get the cells for research or diagnosis and is fraught with risks to the patient as compared with drawing blood. It would be a lot easier if there was a reliable blood test to diagnosis COPD, then we could draw blood from COPD patients and learn whether they have steroid-unresponsive COPD. Cytokines are proteins and like all proteins in the body, they are made from our DNA blueprint in the nucleus of the cell. However, DNA goes through an intermediary called RNA, which then instructs the cell to make the protein. RNA is an important control point for how much protein is actually made: the more stable the RNA molecule, the greater the amount of protein made. Transcription is the process by which DNA makes RNA. Translation is the process by which the cell uses RNA to make protein. We study an RNA binding protein (RBP) called HuR, which binds to the RNA and stabilizes it so that more protein is made. This is called post-transcriptional gene regulation. A useful analogy to better understand the difference between transcription and translation is the light switch and dimmer control: transcription is the light switch and post-transcriptional gene regulation is the dimmer control. In order for the dimmer control to work, the switch must be turned on, but once the switch is on, you can very powerfully control the intensity of the light using the dimmer control. This is exactly analogous to what happens inside the cell: RBPs like HuR function as a dimmer control to increase the amount of cytokines such as IL-17A. We are proposing this study since HuR has been shown to stabilize and control IL-17A RNA in both mice and people and increase its expression. Therefore, it is our idea that the HuR is driving IL-17A expression in steroid-unresponsive COPD, which damages the lungs permanently. Intriguingly, there are drugs that have previously been used in clinical cancer trials in patients that block HuR function; one such drug is called acadesine. If our hypothesis is correct and HuR does control IL-17A in COPD patients, then blocking its action with acadesine may be a novel way of reducing lung inflammation
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010172
Entities
People
- Ulus Atasoy
Organizations
- United States Army
- University of Michigan