Early-life adversity can `get under the skin' and program biological systems, which in turn increases risk for later-life physical and mental-health problems. However, little is known how early-life adversity translates to dynamic cellular responses when facing acute stressors. The goal of this proposal is to identify possible mechanisms involved in young adults. In a uniquely responsive and accessible tissue (peripheral blood mononuclear cells, PBMC), we will measure stress-induced gene expression changes via RNA sequencing over a 4-hour window post-test, as well as inflammatory cytokines (CRP, IL-6, and TNF-?), and PBMC telomerase activity and telomere length. PBMCs show remarkable flexibility in response to stimuli by regulating gene expression in a transient manner. Empirical evidence exist for rapid (e.g., 30 min to 4 hours) PBMC gene expression activation in response to various stressful stimuli in humans. The telomere system has been associated with morbidity and early mortality, as well as early adversity. Mental-health symptoms can influence the course and reactivity of neuroendocrine and autonomic systems, however little is known whether depressive and anxiety symptoms can predict differential gene expression activation following acute stress. The proposed research will be the first to advance understanding of stress-induced gene expression changes, as moderated by previous adversity, shorter telomere length and mental health symptoms.
Aim 1 will test, in a within-subjects design, whether individuals exposed to early-life adversity show dysregulated changes in gene expression and protein levels (cytokines and telomerase) in response to a well- established laboratory stressor (Trier Social Stress Test), compared with a no-stress condition one week apart, and compared with individuals without exposure to early adversity. We predict rapid transcriptomic changes, specifically in glucocorticoid signaling and the conserved transcriptional response to adversity (CTRA) pathways, moderated by exposure to adversity.
Aim 2 will add a measure of telomere length at baseline, as a marker of `exhausted cells', to test whether telomere length can predict differential gene expression activation in response to acute stress. We predict that shorter telomere length at baseline will be associated with greater telomerase activity, as well as transcriptomic changes in telomere-related, senescence and apoptosis pathways.
Aim 3 will examine whether depressive and anxiety symptoms are associated with dysregulated changes in gene expression and protein levels in response to stress. We predict higher levels of depression and anxiety will be associated with dysregulation of glucocorticoid signaling, metabolic and CTRA genes. This innovative study is the first to combine a dynamic RNA sequencing approach with multiple levels of analysis simultaneously, including inflammatory cytokines, telomere length, telomerase activity and mental- health symptoms in the same individuals, as moderated by early adversity. This integrated approach will provide an opportunity to identify dynamic transcriptomic signatures in response to stress that could signal specific profiles of disease risk associated with early-life adversity, as seen, for example, in breast and leukemia cancers. Methodological advances are that the study is a rigorous within-subject experimental design whereas most previous studies have been observational and cross-sectional; repeated measurements of gene expression over ~5 hours using the powerful RNA sequencing approach will enable tests of cellular pathways that are implicated in the etiology of early adversity and mental-health diseases; the data sharing of repeated whole-transcriptomic information will serve as a platform for discovery, transparency and reproducibility; testing moderation effects of early adversity, telomere length and mental-health symptoms will enable us to explore potential programming of biological systems; and measures of telomerase activity enable tests of stress- induced gene expression changes with cellular survival mechanisms. By testing the dynamic stress-induced sequelae of early adversity in young adults the research will identify pathways playing a downstream role in disease susceptibility and accelerated aging. Findings will have important implications for translational science and basic biology. For example, are specific type of interventions (e.g., cognitive-behavioral, mindfulness meditation, pharmacological) mediated through transcriptomic changes? Can these interventions reverse transcriptional patterns implicated in stress-related disorders? And perhaps most importantly, can the interventions be tailored to match the specific cellular processes operating within an individual?
Given the salient role of early-life adversity and the resulting biological embedding in disease risk, there is a critical need to understand the mechanisms operating at multiple levels of analysis in order to promote effective clinical treatments and intervention efforts for survivors. An example for such an effort could be to utilize models of dynamic cellular markers as individual-level factors to account for variation in intervention response and clinical outcomes. Results of this study will lead to new knowledge about specific gene expression pathways in response to stress, and whether the response is moderated by previous exposure to early adversity, shorter telomere length (a marker of cellular aging) and self-report mental-health measures. Thus, the long-term effects of this study will advance our understanding on stress-related transcriptomic changes that play a downstream role in disease susceptibility and accelerated aging, with the goal of targeting specific pathways and genes for potential intervention studies and pharmacological treatments to reverse the effects of exposure to early adversity. For example, considering high failure rates for depression treatments, and in order to tailor individual interventions, identifying objective changes in stress-induced gene expression may help to predict intervention efficacy in clinical and non-clinical settings, as seen, for example, in breast and leukemia cancers. Thus, findings will have a range of impacts for basic science, intervention studies and clinical practice that will influence treatments to match the specific cellular processes operating within an individual.
