Aryl Hydrocarbon Receptor Activation in PTSD and Comorbid Psychological Disorders
Abstract
Post-traumatic stress disorder (PTSD) is one of the major signature injuries of the Iraqi and Afghanistan Wars, and is associated with much personal suffering, poor mental and physical health, and economic cost, and in many cases, depression, shame and self-blame and diminished work performance and quality of personal relationships. While the environmental precipitants of PTSD are clear, the biological factors placing individuals at risk for developing PTSD and those that underlie the progression of PTSD are poorly understood. This lack of adequate understanding of the underlying biology of PTSD largely contributes to the poor rate of remission with current drug treatments; only 30% of treated individuals fully remit with standard medication treatment. This highlights the need to identify new biological mechanisms that underlie PTSD and associated co-occurring conditions such as depression and traumatic brain injury. The identification of these mechanisms should lead to the development of better risk prediction, improved diagnoses, and more effective treatment strategies. One candidate mechanism in the biology of PTSD involves a receptor in certain cells, especially immune cells, that plays an important role in many inflammatory medical conditions, called the Aryl Hydrocarbon Receptor (AhR). We propose that altered activity at this receptor plays a significant role in PTSD, but this has never previously been investigated, despite PTSD having a strong inflammatory aspect. In this proposal, we aim to understand the role of the AhR signaling pathways in the biology of PTSD and associated co-occurring conditions. Studies in animal models of PTSD as well as in people with depression, have suggested this receptor is involved in several symptoms of PTSD. Yet, despite this evidence, the role of this receptor has not been adequately studied in PTSD. As part of the Systems Biology PTSD Biomarkers Consortium, we have access to blood samples of three independent groups of active-duty Soldiers or combat-exposed Veterans who did or did not develop PTSD while in the service, a total of 2,807 subjects. This includes a group of active-duty Soldiers (n=1793) who were evaluated at times prior to deployment and at several times post-deployment. Using a unique cell-based blood test, we will determine if PTSD is associated with greater activation of this receptor compared to individuals who experience combat trauma but did not develop PTSD. In addition, using samples obtained from the same individuals pre- and post-deployment, we will determine if changes in the activity of this receptor are associated with development of PTSD. While different chemicals in the blood can activate this receptor, we will investigate chemicals that are known to activate this receptor and that play a role in a variety of psychiatric diseases (although they have not been specifically studied in PTSD). Specifically, we will measure the blood levels of two broad classes of molecules that are derived from the amino acid tryptophan: kynurenines and indoles. In addition to assessing the activity of this receptor in PTSD, we will determine if the levels of kynurenines and indoles are associated with PTSD and if they predict the development of PTSD. These two sets of studies, assessing the activity of this receptor and the level of chemicals that activate this receptor, we will be able to evaluate the involvement of this receptor system, which has shown prominent involvement in several other medical conditions, in PTSD and co-occurring conditions (major depression and traumatic brain injury). Identifying a role of this receptor in PTSD would substantially alter and improve our understanding of the biology of PTSD and open new doors for the development of new treatments specifically targeted to it. Our study is well aligned with three sub-areas of the Fiscal Year 2021 Traumatic Brain Injury and Psychological Health Idea Development Award Focus Areas. We propose to ident
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210942
Entities
People
- Owen M. Wolkowitz
Organizations
- United States Army
- University of California, San Francisco