This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.This proposal seeks to examine gene-environment interactions that contribute to the development of PTSD in 200 persons selected from a well-characterized sample of 2750 men and women in the New York metropolitan area, exposed to the World Trade Center attacks. This cohort was recruited six months after September 11, has been followed longitudinally for the purpose of determining mental health consequences resulting from this event, and is sufficiently large enough to undertake a comprehensive investigation of risk factors for this disorder. We will examine clinical and neuroendocrine measures previously hypothesized or demonstrated to be associated with risk for PTSD, related to alterations in cortisol signaling. Since genetic factors contribute to the function of this biological system, we will examine polymorphisms of several genes related to glucocorticoid activity, as well as peptidergic and monoaminergic neurotransmission implicated in PTSD pathophysiology. To determine other relevant genes, we will examine expression profiles using microarray techniques and quantitative polymerase chain reaction. The subset of genes that are validated will also be genotyped for association with PTSD. Additionally, based on our recent evidence for non-genetic intergenerational transmission of PTSD and cortisol alterations associated with PTSD (i.e., from trauma-exposed parents with PTSD to their offspring), we will examine stable individual differences in gene activity that are subject to 'programming' by experience via epigenetic mechanisms (e.g., DNA methylation). These studies will focus on specific promoter regions of the glucocorticoid receptor (GR) in lymphocytes, a tissue we have demonstrated to be more responsive to glucocorticoids in PTSD. It will therefore be possible to associate epigenetic alterations in DNA methylation at GR promoter sites with genetic and non-genetic risk factors, and their interaction with trauma severity, towards the aim of understanding the simple, but as yet unanswered question of the role of trauma in the development of PTSD, and possibly the even more complex one of why some persons develop PTSD following trauma exposure while others do not. The coincidence of this unique and representative cohort, together with the expertise reflected in this multi-institutional team, will provide unambiguous information concerning the molecular-genetic basis of PTSD, PTSD vulnerability and even stress resistance. Hypothesis: We hypothesize that PTSD represents a specific phenotype, expressed in the presence of an environmental stressor that is characterized by an inadequate cortisol response at the time of a traumatic event leading (acutely) to an impaired reinstatement of physiologic homeostasis. We have suggested that, at its core, PTSD represents a failure to recover from the normal effects of trauma that can only be explained by models that consider the role of individual differences as modulators of the response to stress. Delineating the contributions of such differences to the development of PTSD, however, requires a broader assessment of vulnerability than has yet been accomplished, ideally including genotypic and molecular measures, in addition to clinical and functional (e.g., neuroendocrine) ones. It is only by examining polymorphisms in genes that are involved in stress-related hormone signaling, and their expression, that we can account for the full range of individual differences in the response to trauma.

National Institute of Health (NIH)
National Center for Research Resources (NCRR)
General Clinical Research Centers Program (M01)
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National Center for Research Resources Initial Review Group (RIRG)
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Mount Sinai School of Medicine
Internal Medicine/Medicine
Schools of Medicine
New York
United States
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