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

AEOP Fellow

Blast-induced traumatic brain injury (bTBI) frequently results in sleep-wake disturbances. However, limited studies have investigated the molecular signaling mechanisms underlying these sleep disturbances, and potentially efficacious therapies are lacking. We investigated the levels of melatonin and genes involved in melatonin synthesis pathway in the pineal glands of Sprague Dawley rats exposed to single and tightly coupled repeated blasts during the night and daytime. Rats were exposed to single and tightly coupled repeated blasts using an advanced blast simulator. The plasma, cerebrospinal fluid (CSF), and pineal gland were collected at 6 h, 24 h, or 1 month postblast at two different time points: one during the day (1000 h) and one at night (2200 h). Differential expressions of genes involved in pineal melatonin synthesis were quantified using quantitative real-time polymerase chain reaction (qRT-PCR). Plasma and CSF melatonin levels were assessed using a commercial melatonin ELISA kit. The plasma and CSF melatonin levels showed statistically significant decreases at 6 h and 24 h in the blast-exposed rats euthanized in the night (in dim light), with no significant alterations noted in rats euthanized in the morning (daylight) at all three-time points. Blast-exposed rats showed statistically significant decreases in Tph1, Aanat, Asmt, and Mtnr1b mRNA levels, along with increased Tph2 mRNA, in the pineal gland samples collected at night at 6 h and 24 h. No significant changes in the mRNA levels of these genes were noted at 1 month. These findings imply that the melatonin circadian rhythm is disrupted following blast exposure, which may be a factor in the sleep disturbances that blast victims frequently experience.

Blast Exposure Dysregulates Nighttime Melatonin Synthesis and Signaling in the Pineal Gland: A Potential Mechanism of Blast-Induced Sleep Disruptions.

Although blast-induced traumatic brain injury (bTBI) has been designated as the signature injury of recent combat operations, its precise pathological mechanism(s) has not been identified thus far. Prior preclinical studies on bTBI demonstrated acute neuroinflammatory cascades which are known to be contributing to neurodegeneration. Danger-associated chemical patterns are released from the injured cells, which activate non-specific pattern recognition receptors, such as toll-like receptors (TLRs) leading to increased expression of inflammatory genes and release of cytokines. Upregulation of specific TLRs in the brain has been described as a mechanism of injury in diverse brain injury models unrelated to blast exposure. However, the expression profile of various TLRs in bTBI has not been investigated thus far. Hence, we have evaluated the expression of transcripts for TLR1-TLR10 in the brain of a gyrencephalic animal model of bTBI. We exposed ferrets to tightly coupled repeated blasts and determined the differential expression of TLRs (TLR1-10) by quantitative RT-PCR in multiple brain regions at 4 hr, 24 hr, 7 days and 28 days post-blast injury. The results obtained indicate that multiple TLRs are upregulated in the brain at 4 hr, 24 hr, 7 days and 28 days post-blast. Specifically, upregulation of TLR2, TLR4 and TLR9 was noted in different brain regions, suggesting that multiple TLRs might play a role in the pathophysiology of bTBI and that drugs that can inhibit multiple TLRs might have enhanced efficacy to attenuate brain damage and thereby improve bTBI outcome. Taken together, these results suggest that several TLRs are upregulated in the brain after bTBI and participate in the inflammatory response and thereby provide new insights into the disease pathogenesis. Therefore, inhibition of multiple TLRs, including TLR2, 4 and 9, simultaneously might be a potential therapeutic strategy for the treatment of bTBI.

Upregulation of multiple toll-like receptors in ferret brain after blast exposure: Potential targets for treatment.

Blast injury has been implicated as the major cause of traumatic brain injury (TBI) and ocular system injury, in military operations in Iraq and Afghanistan. Soldiers exposed to traumatic stress also have undiagnosed, chronic vision problems. Here we hypothesize that excessive intake of ω-6 fatty acid linoleic acid (LA) and insufficiency of dietary long chain ω-3 polyunsaturated fatty acids (PUFAs, e.g., docosahexaenoic acid; DHA) would dysregulate endocannabinoid-mediated neuronal plasticity and immune response. The study objective was to determine the effect of blast-TBI and traumatic stress on retinal gene expression and assess the role of dietary deficiency of long chain ω-3 PUFAs on the vulnerability to these injury models.

Article	Year
Blast Exposure Dysregulates Nighttime Melatonin Synthesis and Signaling in the Pineal Gland: A Potential Mechanism of Blast-Induced Sleep Disruptions. Brain sciences\| PubMed ID: 36291274	2022
Upregulation of multiple toll-like receptors in ferret brain after blast exposure: Potential targets for treatment. Neuroscience letters\| PubMed ID: 37391063	2023
Impact of dietary changes on retinal neuronal plasticity in rodent models of physical and psychological trauma. Frontiers in genetics\| PubMed ID: 39346777	2024

Mital Y. Patel

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