Understanding Gene x Stress Interactions Across the Cell Types of the Brain in PTSD
Abstract
Background: The projects in this proposal are designed to increase our understanding of how trauma impacts combat Veterans based on their unique genetics. It is well known that not all persons who are exposed to combat trauma develop PTSD. It is also now accepted that pre-existing risk factors play an important role in determining who might develop PTSD. It is important to not only identify these risk factors, but to understand how they work to produce psychological symptoms. There have been many studies that have sought to develop objective laboratory blood tests that could be used to diagnose PTSD, measure the severity of PTSD symptoms, or confirm recovery. Many of these lab tests have examined the expression of genes and how it differs in people with PTSD. But these studies are highly limited because a true understanding of how genes interact with trauma to produce PTSD requires examination of how genes function in brain cells. Until recently, there has been no way to really do this in living people. However, work done by our group over the last few years has changed that. Using the latest developments in stem cell technology, we took skin cells from combat Veterans with and without PTSD, reprogrammed them into pluripotent stem cells, and then differentiated them into brain cells (neurons). We added stress hormones to the dish with the brain cells and were able to observe differences in gene expression in the cells from 50 Veterans with and without PTSD. In this proposal we build on those findings with four separate projects. In Project 1, we will recruit more participants so that we can double our sample size and increase our confidence in our observations. We will attempt to duplicate our prior results in two types of neurons – excitatory and inhibitory ones – and ask important follow-up questions, including those relating to sex differences in genetic risk. In Project 2, we will use the previously collected samples to differentiate the stem cells into different types of brain cells – astrocytes – and create organoids, which are functional collections of many kinds of brain cells, including different types of neurons and glial cells, in the dish. We will be able to then see whether gene expression profiles vary in different brain cell types, and how these changes may work together in an overall preparation with many cell types. In Project 3, we will manipulate the precise risk variants and genes associated with PTSD across all the major cell types of the brain – neurons, astrocytes, and microglia –allowing us to examine how the downstream impacts of these genes interact and converge in response to stress hormones in the test tube. This will be an important independent validation and extension of previous work. In Project 4, we will use sophisticated computational analyses to examine the clinical consequences of gene x environment interactions by comparing our results with those of two large healthcare and population-based brain banks. This will allow us to pinpoint which genes are important to the expression of PTSD symptoms and will give us critical information to establish a personalized medicine approach to PTSD treatment in the future. The results of these studies will help us understand how PTSD develops in the first place, enabling us to identify and prioritize biological targets and pathways for therapeutic intervention. This will lead to unprecedented, useful clinically actionable insights for servicepersons and society. Project 1 Only a minority of people exposed to trauma will end up with PTSD, and it remains unclear why this is, or how to effectively treat it. Historically, cellular studies of PTSD have been conducted on blood samples, but as the brain is the primarily affected organ, it is critical to understand the changes that occur in brain cells. Reprogramming skin cells into stem cells makes it possible to generate live human neurons that are genetically identical to those i
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252311068
Entities
People
- Rachel Yehuda
Organizations
- Icahn School of Medicine at Mount Sinai
- United States Army