Grant: $499,960 - National Institutes of Health - Sep. 25, 2009
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Award Description: This grant responds to NIH Challenge 08-MH-103: Understanding the Genomic Risk Architecture of Mental Disorders. This application builds on recent animal and human data on epigenetic mechanisms mediating 'glucocorticoid programming' to address a critical gap in knowledge about how early experience confers increased biological risk for post-traumatic stress disorder (PTSD). The gap in knowledge will be addressed by examining cytosine methylation of the glucocorticoid receptor (GR) gene. The study of epigenetic modifications in relation to PTSD risk represents an important scientific frontier. PTSD occurs in only a proportion of those exposed to trauma, but has a population lifetime prevalence of 10-14%. Maternal PTSD has been identified as a risk factor for PTSD in 2nd generation offspring (F2) allowing examination of biological mechanisms in association with this risk factor. The GR gene is the focus of investigation because alterations reflecting enhanced GR responsiveness have been demonstrated in F2 with maternal PTSD, and in other PTSD samples.The relationships among cytosine methylation, GR gene expression, and neuroendocrine measures associated with PTSD risk (GR sensitivity, negative feedback inhibition, basal cortisol level and metabolism) will be examined in 120 F2 of Holocaust survivors (grouped by presence or absence of maternal and paternal PTSD) and in 30 subjects with no parental Holocaust exposure or PTSD. Since glucocorticoid programming has also been implicated as a mechanism through which [in utero] maternal stress increases risk for the subsequent development of metabolic syndrome (MetS) in their adult offspring, and recent data have linked PTSD to the development of MetS and its consequences, data on MetS will also be obtained. This project can be accomplished in two years because we can recruit from previously studied Holocaust F2 that agreed to be recontacted. Cytosine methylation will be quantified using polymerase chain reaction (PCR) primers developed by Michael Meaney, Ph.D. that selectively amplify variations in the relevant region of the GR gene for DNA methylation and splice variant analysis of mRNA in the human lymphocyte. Dr. Meaney's group has confirmed that the organization of the human GR gene closely resembles the rat GR. Our primary hypothesis is that cytosine methylation will be greater in F2 with maternal than paternal PTSD. A path analysis model will examine the contribution of this epigenetic modification to neuroendocrine and metabolic consequences associated with PTSD risk, incorporating other relevant aspects of early life experience (parental symptoms, childhood abuse and neglect, parental care and overprotection) to assess their contribution. This work is innovative in attempting to use a naturalistic intergenerational 'model system' to examine the role for an epigenetic mechanism in transmitted vulnerability for PTSD and associated health risks, and determine their relationship to other environmental contributors. The results have implications for detecting persons at risk for PTSD, but may also point to novel targets for prophylaxis and early treatment. Adult children of mothers with post traumatic stress disorder (PTSD) are at increased risk for PTSD, and also show changes in their responsiveness to the stress hormone cortisol that appear to reflect early developmental influences, possibly resulting from maternal stress effects. In this grant we investigate whether the biological changes in these offspring reflect an enduring epigenetic modification, induced by early maternal behavior that resulted in 'recalibrating' the cortisol system in a manner that increases risk for subsequent PTSD and possibly other health consequences. If such changes are observed, this research will yield an early (i.e., pretraumatic) biologic marker that can ultimately be used in screening persons at increased risk for PTSD either before or immediately after they are exposed to trauma.
Project Description: As defined in the Award Description field.
Jobs Summary: N/A (Total jobs reported: 0)
Project Status: Not Started
This award's data was last updated on Sep. 25, 2009. Help expand these official descriptions using the wiki below.