Periodic Reporting for period 1 - TraumiR (microRNAs in susceptibility to traumatic stress)
Berichtszeitraum: 2016-06-01 bis 2018-05-31
Post-traumatic stress disorder (PTSD) is a psychiatric disorder that can manifest itself following exposure to a threatening traumatic event such as combat, assault or a natural disaster. The disease is characterized by symptoms including re-experiencing of the traumatic event through flashbacks or recurrent nightmares, constant avoidance of reminders of the event, negative mood, and extreme arousal. These symptoms can manifest itself through insomnia or hyper-alertness and may last for a very long time, which significantly affects the quality of life of PTSD patients. Individuals with PTSD are six times more at risk of committing suicide and having marital problems, and the annual loss of productivity is estimated to be approximately $3 billion. Currently, there is no definite cure for patients with PTSD, and available treatments often are not effective.
Within the general population, it is relatively common to be exposed to a traumatic event over the course of one’s lifetime (40–90%), but only a fraction of individuals (7% and 12%) will develop PTSD while others will adapt to the situation and maintain proper mental health. The identification of markers that distinguish persons at high and low risk of developing PTSD following trauma exposure would enable more effective preventive strategies and early interventions.
Little is known regarding the mechanisms behind these different responses. During the last few years, increasing attention has been given to whether the modification of genes expression in the form of epigenetic mechanisms might be involved. Among epigenetic mechanisms, microRNAs (miRNA, Micro RiboNucleic Acids) are gaining attention. MiRNAs are small molecules with chemical building blocks similar to DNA. Unlike the more famous DNA, miRNAs are typically very short – comprising only around 20 to 25 base units (the building blocks of nucleic acids), and are non-coding. In other words, they do not specify the production of a protein or peptide. However, they have very important roles in biology since every miRNA regulates the expression, and thereby also the activity of several other genes, and are known to regulate the impact of environmental factors on biology. In addition, brain-derived miRNAs can circulate throughout the human body and can be detected in the blood. Differences in miRNA levels have been associated with certain diseases, such as some cancers, kidney disease, alcoholism and even depression. This regulatory role makes them a candidate for investigation in PTSD. However, there are several practical and ethical challenges in designing a research study on humans undergoing such experiences, meaning that designing relevant study approaches is difficult.
Based on this and the emerging role of miRNAs as key epigenetic players in psychiatric disorders, we aimed to determine the role of miRNAs in the susceptibility for developing PTSD after being exposed to traumatic stress. More specifically, the two key objectives were (1) to identify miRNA candidates associated with differential susceptibility to develop PTSD after traumatic stress exposure in humans and mice and (2) to test the effect of manipulating the expression of candidate miRNAs on the susceptibility to traumatic stress exposure in mice.
Within the general population, it is relatively common to be exposed to a traumatic event over the course of one’s lifetime (40–90%), but only a fraction of individuals (7% and 12%) will develop PTSD while others will adapt to the situation and maintain proper mental health. The identification of markers that distinguish persons at high and low risk of developing PTSD following trauma exposure would enable more effective preventive strategies and early interventions.
Little is known regarding the mechanisms behind these different responses. During the last few years, increasing attention has been given to whether the modification of genes expression in the form of epigenetic mechanisms might be involved. Among epigenetic mechanisms, microRNAs (miRNA, Micro RiboNucleic Acids) are gaining attention. MiRNAs are small molecules with chemical building blocks similar to DNA. Unlike the more famous DNA, miRNAs are typically very short – comprising only around 20 to 25 base units (the building blocks of nucleic acids), and are non-coding. In other words, they do not specify the production of a protein or peptide. However, they have very important roles in biology since every miRNA regulates the expression, and thereby also the activity of several other genes, and are known to regulate the impact of environmental factors on biology. In addition, brain-derived miRNAs can circulate throughout the human body and can be detected in the blood. Differences in miRNA levels have been associated with certain diseases, such as some cancers, kidney disease, alcoholism and even depression. This regulatory role makes them a candidate for investigation in PTSD. However, there are several practical and ethical challenges in designing a research study on humans undergoing such experiences, meaning that designing relevant study approaches is difficult.
Based on this and the emerging role of miRNAs as key epigenetic players in psychiatric disorders, we aimed to determine the role of miRNAs in the susceptibility for developing PTSD after being exposed to traumatic stress. More specifically, the two key objectives were (1) to identify miRNA candidates associated with differential susceptibility to develop PTSD after traumatic stress exposure in humans and mice and (2) to test the effect of manipulating the expression of candidate miRNAs on the susceptibility to traumatic stress exposure in mice.
In order to identify miRNA candidate molecules associated with the susceptibility to develop PTSD after exposure to traumatic stress in humans, we used blood samples from a large cohort of just over 1,000 Dutch military personnel deployed to an activa war zone in Afghanistan. These soldiers were followed over time and blood samples were collected before deployment, as well as 6 months after deployment. Most of the soldiers have been exposed to trauma, and some of them have developed symptoms of PTSD (susceptible persons) while other maintained mental health (resilient persons). We first started with a pilot study in which subgroups were selected of a total of 24 subjects; 8 of the soldiers had developed symptoms of PTSD; 8 had endorsed traumatic experiences but had not developed such symptoms; and another 8 had not been in serious traumatic circumstances and served as a control group. Using modern sequencing techniques and bioinformatics tools, several types of miRNAs of which the blood levels differed between the groups were identified: 32 of them were regulated differently in people who developed PTSD, whereas 15 of the miRNAs were differently expressed in trauma-exposed individuals who did not develop PTSD as compared to non-trauma exposed controls. In an attempt to identify relevant cross-species miRNA candidates, we compared our human results to the ones obtained from the blood of three animal models of PTSD and found common miRNA between mice and humans. These results were further compared to miRNA profilesin the amygdala, a brain region involved in PTSD development, leading to the selection of one potential miRNA to explore further. Specifically, the amount of that miRNA was manipulated in the amygdala of mice (increasing or decreasing its quantity) suffering from the animal equivalent of PTSD. As a result, we demonstrated that this miRNA regulates stress-related abnormal memory associated with PTSD. These interesting results are currently replicated and validated in another US cohort of Marine veterans.
The relevance of obtaining a better understanding of stress-related disorders is unfortunately becoming clearer and clearer after each terror attack. This work points to an innovative avenue regarding the identification of potential risk factors for susceptibility to developing PTSD. Besides providing original knowledge for understanding the biological mechanisms underlying differential susceptibility to traumatic stress, our project established a first step toward clinical applications. The project identified that miRNA profiles in blood can predict susceptibility to traumatic stress and that miRNAs could potentially serve as biomarkers. Moreover, this work is therapeutically relevant as it can lead to the development of small molecules inhibiting specific miRNAs that could have potential therapeutic value.
Although interesting, these preliminary results still need to be validated and replicated in other human cohorts before any initial phase of clinical application can start. For future perspective, one could imagine that susceptible people could be differentiated from resilient ones through a simple blood test. Given the relatively simple and objective measurement of miRNAs in blood, this screening method seems applicable to large communities, and may thus have enormous impact on populations at risk for exposure. Given the high prevalence and enormous burden of PTSD, a potential reduction of 5% of the incidence of PTSD will already have a vast impact on health and society.
Although interesting, these preliminary results still need to be validated and replicated in other human cohorts before any initial phase of clinical application can start. For future perspective, one could imagine that susceptible people could be differentiated from resilient ones through a simple blood test. Given the relatively simple and objective measurement of miRNAs in blood, this screening method seems applicable to large communities, and may thus have enormous impact on populations at risk for exposure. Given the high prevalence and enormous burden of PTSD, a potential reduction of 5% of the incidence of PTSD will already have a vast impact on health and society.