Dataset Information

Identification of target genes in neuroinflammation and neurodegeneration after traumatic brain injury in rats.

ABSTRACT: Background:Traumatic brain injury (TBI) is a common neurological emergency observed in hospitals. A considerable number of patients suffer from long-term disabilities after TBI. This study aimed to identify altered gene expression signatures and mechanisms related to TBI-induced chronic neuroinflammation and neurodegeneration. Methods:An integrated analysis was performed using published RNA-sequencing studies to determine TBI-induced differentially expressed genes (DEGs). Based on the DEG data, functional annotation, signal-net, and transcription factor analyses were conducted to understand the mechanism of chronic neuroinflammation and neurodegeneration induced after TBI. Results:Two datasets were obtained using the Gene Expression Omnibus database, of which, 6,513 DEGs were identified (6,464 upregulated and 49 downregulated). Positive regulation of biological process, positive regulation of cellular process, nucleus, and heterocyclic compound binding were Gene Ontology terms significantly enriched in post-TBI rat models. Leukocyte transendothelial migration, chemokine signaling pathway, neurotrophin signaling pathway, and longevity-regulating pathway were significantly enriched after TBI. With regard to the signal-net analysis, FOXO3, DGKZ and ILK were considered the most critical genes derived using high-betweenness centrality calculation. A total of 44 TFs, including FOXO1, SRY and KLF4, were predicted to play an important role in the upregulation of gene expression. Using integrated bioinformatics analysis, TBI was found to be associated with a significant inflammatory response and neurodegeneration. FOXO3, apolipoprotein (APOE), microtubule-associated protein tau (MAPT), and TREM2 were probably associated with the TBI pathological process. The mitochondrial electron transport chain may be associated with neurodegeneration in patients with TBI, serving as a potential therapeutic target.

SUBMITTER: Zhao J

PROVIDER: S-EPMC6925952 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Identification of target genes in neuroinflammation and neurodegeneration after traumatic brain injury in rats.

Zhao Jianwei J Xu Chen C Cao Heli H Zhang Lin L Wang Xuyang X Chen Shiwen S

PeerJ 20191219

<h4>Background</h4>Traumatic brain injury (TBI) is a common neurological emergency observed in hospitals. A considerable number of patients suffer from long-term disabilities after TBI. This study aimed to identify altered gene expression signatures and mechanisms related to TBI-induced chronic neuroinflammation and neurodegeneration.<h4>Methods</h4>An integrated analysis was performed using published RNA-sequencing studies to determine TBI-induced differentially expressed genes (DEGs). Based on ...[more]

PMID: 31875163

Similar Datasets

Project description:ObjectiveTraumatic brain injury (TBI) is a heterogeneous disease with multiple neurological deficits that evolve over time. It is also associated with an increased incidence of neurodegenerative diseases. Accordingly, clinicians need better tools to predict a patient's long-term prognosis.MethodsDiffusion-weighted and anatomical MRI data were collected from 17 adolescents (mean age = 15y8mo) with moderate-to-severe TBI and 19 healthy controls. Using a network diffusion model (NDM), we examined the effect of progressive deafferentation and gray matter thinning in young TBI patients. Moreover, using a novel automated inference method, we identified several injury epicenters in order to determine the neural degenerative patterns in each TBI patient.ResultsWe were able to identify the subject-specific patterns of degeneration in each patient. In particular, the hippocampus, temporal cortices, and striatum were frequently found to be the epicenters of degeneration across the TBI patients. Orthogonal transformation of the predicted degeneration, using principal component analysis, identified distinct spatial components in the temporal-hippocampal network and the cortico-striatal network, confirming the vulnerability of these networks to injury. The NDM model, best predictive of the degeneration, was significantly correlated with time since injury, indicating that NDM can potentially capture the pathological progression in the chronic phase of TBI.InterpretationThese findings suggest that network spread may help explain patterns of distant gray matter thinning, which would be consistent with Wallerian degeneration of the white matter connections (i.e., "diaschisis") from diffuse axonal injuries and multifocal contusive injuries, and the neurodegenerative patterns of abnormal protein aggregation and transmission, which are hallmarks of brain changes in TBI. NDM approaches could provide highly subject-specific biomarkers relevant for disease monitoring and personalized therapies in TBI.

Project description:BACKGROUND:Understanding the interdependencies among inflammatory mediators of tissue damage following traumatic brain injury (TBI) is essential in providing effective, patient-specific care. Activated microglia and elevated concentrations of inflammatory signaling molecules reflect the complex cascades associated with acute neuroinflammation and are predictive of recovery after TBI. However, clinical TBI studies to date have not focused on modeling the dynamic temporal patterns of simultaneously evolving inflammatory mediators, which has potential in guiding the design of future immunomodulation intervention studies. METHODS:We derived a mathematical model consisting of ordinary differential equations (ODE) to represent interactions between pro- and anti-inflammatory cytokines, M1- and M2-like microglia, and central nervous system (CNS) tissue damage. We incorporated variables for several cytokines, interleukin (IL)-1?, IL-4, IL-10, and IL-12, known to have roles in microglial activation and phenotype differentiation. The model was fit to cerebrospinal fluid (CSF) cytokine data, collected during the first 5 days post-injury in n?=?89 adults with severe TBI. Ensembles of model fits were produced for three patient subgroups: (1) a favorable outcome group (GOS?=?4,5) and (2) an unfavorable outcome group (GOS?=?1,2,3) both with lower pro-inflammatory load, and (3) an unfavorable outcome group (GOS?=?1,2,3) with higher pro-inflammatory load. Differences in parameter distributions between subgroups were ranked using Bhattacharyya metrics to identify mechanistic differences underlying the neuroinflammatory patterns of patient groups with different TBI outcomes. RESULTS:Optimal model fits to data showed different microglial and damage responses by patient subgroup. Upon comparison of model parameter distributions, unfavorable outcome groups were characterized by either a prolonged, pathophysiological or a transient, sub-physiological course of neuroinflammation. CONCLUSION:By developing a mathematical characterization of inflammatory processes informed by clinical data, we have created a system for exploring links between acute neuroinflammatory components and patient outcome in severe TBI.

Project description:Traumatic brain injury (TBI) increases Ca2+ influx into neurons and desynchronizes mitochondrial function leading to energy depletion and apoptosis. This process may be influenced by brain testosterone (TS) levels, which are known to decrease after TBI. We hypothesized that a TS-based therapy could preserve mitochondrial neuroenergetics after TBI, thereby reducing neurodegeneration. C57BL/6J mice were submitted to sham treatment or severe parasagittal controlled cortical impact (CCI) and were subcutaneously injected with either vehicle (VEH-SHAM and VEH-CCI) or testosterone cypionate (15 mg/kg, TS-CCI) for 10 days. Cortical tissue homogenates ipsilateral to injury were used for neurochemical analysis. The VEH-CCI group displayed an increased Ca2+-induced mitochondrial swelling after the addition of metabolic substrates (pyruvate, malate, glutamate, succinate, and adenosine diphosphate [PMGSA]). The addition of Na+ stimulated mitochondrial Ca2+ extrusion through Na+/Ca2+/Li+ exchanger (NCLX) in VEH-SHAM and TS-CCI, but not in the VEH-CCI group. Reduction in Ca2+ efflux post-injury was associated with impaired mitochondrial membrane potential formation/dissipation, and decreased mitochondrial adenosine triphosphate (ATP)-synthase coupling efficiency. Corroborating evidence of mitochondrial uncoupling was observed with an increase in H2O2 production post-injury, but not in superoxide dismutase (SOD2) protein levels. TS administration significantly reduced these neuroenergetic alterations. At molecular level, TS prevented the increase in pTauSer396 and alpha-Spectrin fragmentation by the Ca2+dependent calpain-2 activation, and decreased both caspase-3 activation and Bax/BCL-2 ratio, which suggests a downregulation of mitochondrial apoptotic signals. Search Tool for the Retrieval of Interacting Genes/Proteins database provided two distinct gene/protein clusters, "upregulated and downregulated," interconnected through SOD2. Therefore, TS administration after a severe CCI improves the mitochondrial Ca2+extrusion through NCLX exchanger and ATP synthesis efficiency, ultimately downregulating the overexpression of molecular drivers of neurodegeneration.

Dataset Information

Identification of target genes in neuroinflammation and neurodegeneration after traumatic brain injury in rats.

Publications

Identification of target genes in neuroinflammation and neurodegeneration after traumatic brain injury in rats.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets