elucidating-tissue-plasma-specific-proteomic-alterations-health

Elucidating Tissue- and Plasma-Specific Proteomic Alterations in Health and Disease

Proteomics is the large-scale study of expressed proteins, focusing on their structure, function, interactions, abundance, and post-translational ...

Walter Reed Army Institute of Research

Culmen International, LLC

Post-traumatic stress disorder (PTSD) is a highly debilitating psychiatric disorder that can be triggered by exposure to extreme trauma. Even if PTSD is primarily a psychiatric condition, it is also characterized by adverse somatic comorbidities. One illness commonly co-occurring with PTSD is Metabolic syndrome (MetS), which is defined by a set of health risk/resilience factors including obesity, elevated blood pressure, lower high-density lipoprotein cholesterol, higher low-density lipoprotein cholesterol, higher triglycerides, higher fasting blood glucose and insulin resistance. Here, phenotypic association between PTSD and components of MetS are tested on a military veteran cohort comprising chronic PTSD presentation ( = 310, 47% cases, 83% male). Consistent with previous observations, we found significant phenotypic correlation between the various components of MetS and PTSD severity scores. To examine if this observed symptom correlations stem from a shared genetic background, we conducted genetic correlation analysis using summary statistics data from large-scale genetic studies. Our results show robust positive genetic correlation between PTSD and MetS (r[SE] = 0.33 [0.056],  = 4.74E-09), and obesity-related components of MetS (r = 0.25, SE = 0.05,  = 6.4E-08). Prioritizing genomic regions with larger local genetic correlation implicate three significant loci. Overall, these findings show significant genetic overlap between PTSD and MetS, which may in part account for the markedly increased occurrence of MetS among PTSD patients.

The Genetic Basis for the Increased Prevalence of Metabolic Syndrome among Post-Traumatic Stress Disorder Patients.

Post-traumatic stress disorder (PTSD) is a multisystem syndrome. Integration of systems-level multi-modal datasets can provide a molecular understanding of PTSD. Proteomic, metabolomic, and epigenomic assays are conducted on blood samples of two cohorts of well-characterized PTSD cases and controls: 340 veterans and 180 active-duty soldiers. All participants had been deployed to Iraq and/or Afghanistan and exposed to military-service-related criterion A trauma. Molecular signatures are identified from a discovery cohort of 218 veterans (109/109 PTSD+/-). Identified molecular signatures are tested in 122 separate veterans (62/60 PTSD+/-) and in 180 active-duty soldiers (PTSD+/-). Molecular profiles are computationally integrated with upstream regulators (genetic/methylation/microRNAs) and functional units (mRNAs/proteins/metabolites). Reproducible molecular features of PTSD are identified, including activated inflammation, oxidative stress, metabolic dysregulation, and impaired angiogenesis. These processes may play a role in psychiatric and physical comorbidities, including impaired repair/wound healing mechanisms and cardiovascular, metabolic, and psychiatric diseases.

Molecular signatures of post-traumatic stress disorder in war-zone-exposed veteran and active-duty soldiers.

Metabolomics, proteomics and DNA methylome assays, when done in tandem from the same blood sample and analyzed together, offer an opportunity to evaluate the molecular basis of post-traumatic stress disorder (PTSD) course and pathogenesis. We performed separate metabolomics, proteomics, and DNA methylome assays on blood samples from two well-characterized cohorts of 159 active duty male participants with relatively recent onset PTSD (<1.5 years) and 300 male veterans with chronic PTSD (>7 years). Analyses of the multi-omics datasets from these two independent cohorts were used to identify convergent and distinct molecular profiles that might constitute potential signatures of severity and progression of PTSD and its comorbid conditions. Molecular signatures indicative of homeostatic processes such as signaling and metabolic pathways involved in cellular remodeling, neurogenesis, molecular safeguards against oxidative stress, metabolism of polyunsaturated fatty acids, regulation of normal immune response, post-transcriptional regulation, cellular maintenance and markers of longevity were significantly activated in the active duty participants with recent PTSD. In contrast, we observed significantly altered multimodal molecular signatures associated with chronic inflammation, neurodegeneration, cardiovascular and metabolic disorders, and cellular attritions in the veterans with chronic PTSD. Activation status of signaling and metabolic pathways at the early and late timepoints of PTSD demonstrated the differential molecular changes related to homeostatic processes at its recent and multi-system syndromes at its chronic phase. Molecular alterations in the recent PTSD seem to indicate some sort of recalibration or compensatory response, possibly directed in mitigating the pathological trajectory of the disorder.

Integrated analysis of proteomics, epigenomics and metabolomics data revealed divergent pathway activation patterns in the recent versus chronic post-traumatic stress disorder.

The identification of immune correlates of protection against infectious pathogens will accelerate the design and optimization of recombinant and subunit vaccines. Systematic analyses such as immunoprofiling including serological, cellular, and molecular assessments supported by computational tools are key to not only identify correlates of protection but also biomarkers of disease susceptibility. The current study expands our previous cellular and serological profiling of vaccine-induced responses to a whole parasite malaria vaccine. The irradiated sporozoite model was chosen as it is considered the most effective vaccine against malaria. In contrast to whole blood transcriptomics analysis, we stimulated peripheral blood mononuclear cells (PBMC) with sporozoites and enriched for antigen-specific cells prior to conducting transcriptomics analysis. By focusing on transcriptional events triggered by antigen-specific stimulation, we were able to uncover quantitative and qualitative differences between protected and non-protected individuals to controlled human malaria infections and identified differentially expressed genes associated with sporozoite-specific responses. Further analyses including pathway and gene set enrichment analysis revealed that vaccination with irradiated sporozoites induced a transcriptomic profile associated with Th1-responses, Interferon-signaling, antigen-presentation, and inflammation. Analyzing longitudinal time points not only post-vaccination but also post-controlled human malaria infection further revealed that the transcriptomic profile of protected vs non-protected individuals was not static but continued to diverge over time. The results lay the foundation for comparing protective immune signatures induced by various vaccine platforms to uncover immune correlates of protection that are common across platforms.

Human transcriptional signature of protection after  immunization and infectious challenge  mosquito bites.

Acute Stress Disorder (ASD) is a psychiatric condition that can develop shortly after trauma exposure. Although molecular studies of ASD are only beginning, groups of metabolites have been found to be significantly altered with acute stress phenotypes in various pre-clinical and clinical studies. ASD implicated metabolites include amino acids (β-hydroxybutyrate, glutamate, 5-aminovalerate, kynurenine and aspartate), ketone bodies (β-hydroxybutyrate), lipids (cortisol, palmitoylethanomide, and N-palmitoyl taurine) and carbohydrates (glucose and mannose). Network and pathway analysis with the most prominent metabolites shows that Extracellular signal-regulated kinases and c-AMP response element binding (CREB) protein can be crucial players. After highlighting main recent findings on the role of metabolites in ASD, we will discuss potential future directions and challenges that need to be tackled. Overall, we aim to showcase that metabolomics present a promising opportunity to advance our understanding of ASD pathophysiology as well as the development of novel biomarkers and therapeutic targets.

Exploring metabolomic dynamics in acute stress disorder: amino acids, lipids, and carbohydrates.

A dysregulated immune response after severe burn injury is associated with detrimental short and long-term clinical outcomes. Key changes to gene expression within the first 24 h after burn injury have been identified, but longitudinal data is lacking. Therefore, this study aims to characterize gene expression during the first 3 weeks after burn injury and identify specific genes and pathways associated with distinct clinical outcomes. Patients presenting within 4 h of injury had blood RNA isolated for microarray gene expression at admission and set timepoints to 21 days. Inter- and intra-group comparisons were performed between 4 groups (G1 died within 7 days; G2 died after 7 days; G3 discharged after 7 days; and G4 discharged within 7 days). A total of 17 289 transcripts were quantified from 116 patients. At admission, there were 110, 80, and 31 differentially expressed genes in G1, G2, and G3, respectively, compared to G4, and were largely nonoverlapping. Longitudinal intra-group analyses also showed distinct group- and time-dependent patterns. Upregulation of genes and pathways related to the innate immune response and unfolded protein response predominated during early time points, while persistent upregulation of coagulation pathways and downregulation of immune-related pathways were identified days to weeks following injury. Overall, burn injury induces widespread transcriptomic responses, with larger and more sustained changes observed in patients with worse clinical outcomes. These gene expression signatures reveal underlying molecular mechanisms that occur immediately following injury and may have prognostic and diagnostic utility in the care of burn-injured patients.

Article	Year
The Genetic Basis for the Increased Prevalence of Metabolic Syndrome among Post-Traumatic Stress Disorder Patients. International journal of molecular sciences\| PubMed ID: 36293361	2022
Molecular signatures of post-traumatic stress disorder in war-zone-exposed veteran and active-duty soldiers. Cell reports. Medicine\| PubMed ID: 37196634	2023
Integrated analysis of proteomics, epigenomics and metabolomics data revealed divergent pathway activation patterns in the recent versus chronic post-traumatic stress disorder. Brain, behavior, and immunity\| PubMed ID: 37516387	2023
Human transcriptional signature of protection after immunization and infectious challenge mosquito bites. Human vaccines & immunotherapeutics\| PubMed ID: 38010150	2023
Exploring metabolomic dynamics in acute stress disorder: amino acids, lipids, and carbohydrates. Frontiers in genetics\| PubMed ID: 39119583	2024
Distinct Transcriptome Signatures Associated With Mortality and Prolonged Recovery Following Burn Injury. Journal of burn care & research : official publication of the American Burn Association\| PubMed ID: 40397518	2025

Burook Misganaw

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