A Systems Approach to Dissecting Immune Gene Regulatory Networks in the Modulation of Brain Function

Although the central nervous system was long perceived as the ivory tower without immune entities, there is growing evidence that the immune and nervous systems are intimated connected. These two systems have been shown to communicate both cellularly and molecularly under physiological and pathological conditions. Despite our increasing understanding of the interplay between these two systems, there are still numerous open questions. In this thesis, I address such unanswered questions related to: the role of microglia and their mechanism in contributing to pathologies in Rett syndrome; the beneficial effects of T-cell secreted cytokines in supporting social brain function; the evolutionary link of the interactions between the nervous and immune systems; the transcription regulation of a subset of microglia population in common neurodegenerative diseases. Collectively, the current thesis is focused on the joint frontier of bioinformatics and experimental work in neuroimmunology. A multifaceted approach, that includes transcriptomics, genomics and other biomolecular modules, was implemented to unearth signaling pathways and mechanisms underlying the presenting biological phenomena. The findings of this thesis can be summarized as follows: 1) MeCP2 acts as a master regulator in the transcriptional repression of inflammatory stimuli in macrophages; 2) T-cell secreted IFN-γ supports social brain function through an evolutionally conserved interaction between the immune and nervous systems; 3) The APOE-TREM2 pathway regulates the microglia phenotype switch in neurodegenerative diseases. Provided that recent technologies allow for readily manipulating the immune system, the findings presented herein may create new vistas for therapeutic interventions in various neurological disorders

Comprehensive assessment of shockwave intensity: Transcriptomic biomarker discovery for primary blast-induced mild traumatic brain injury using the mammalian hair follicle

<p><i>Objective</i>: Primary blast-induced mild traumatic brain injury (mTBI) is an injury experienced during modern warfare due to exposure to the pressure waves produced by the detonation of explosives. With virtually no apparent physical damage or symptoms presented, there is a need for more objective and accessible mTBI biomarkers posing minimal invasiveness risk.</p> <p><i>Methods</i>: We measured the transcriptomic sensitivity of the hair follicles in relation to the severity of primary blast-derived TBI. An Advanced Blast Simulator system was used to expose male rats to single pulse shock waves (intensities ranging from 15 to 30 psi) in a head-only fashion. Gene differential expression (DE) and gene set (GS) analyses were conducted in the rat whisker hair follicles and the whole blood samples.</p> <p><i>Results</i>: While shared cellular function, themes were found across the exposure groups, some gene sets under such themes were unique to the exposure conditions. Intensity-specific pathway enrichment patterns within shared GS themes were also identified. Furthermore, while exhibited shared pathways, the blood transcriptome showed substantially fewer enriched gene sets compared with the hair follicles across all exposure conditions.</p> <p><i>Conclusions</i>: Accordingly, we demonstrate the potential of mammalian hair follicles serving as an additional source for biomarker discovery and for diagnosing mTBI with high accessibility.</p

Transcriptional Profiling in Rat Hair Follicles following Simulated Blast Insult: A New Diagnostic Tool for Traumatic Brain Injury

<div><p>With wide adoption of explosive-dependent weaponry during military activities, Blast-induced neurotrauma (BINT)-induced traumatic brain injury (TBI) has become a significant medical issue. Therefore, a robust and accessible biomarker system is in demand for effective and efficient TBI diagnosis. Such systems will also be beneficial to studies of TBI pathology. Here we propose the mammalian hair follicles as a potential candidate. An Advanced Blast Simulator (ABS) was developed to generate shock waves simulating traumatic conditions on brains of rat model. Microarray analysis was performed in hair follicles to identify the gene expression profiles that are associated with shock waves. Gene set enrichment analysis (GSEA) and sub-network enrichment analysis (SNEA) were used to identify cell processes and molecular signaling cascades affected by simulated bomb blasts. Enrichment analyses indicated that genes with altered expression levels were involved in central nervous system (CNS)/peripheral nervous system (PNS) responses as well as signal transduction including Ca²⁺, K⁺-transportation-dependent signaling, Toll-Like Receptor (TLR) signaling and Mitogen Activated Protein Kinase (MAPK) signaling cascades. Many of the pathways identified as affected by shock waves in the hair follicles have been previously reported to be TBI responsive in other organs such as brain and blood. The results suggest that the hair follicle has some common TBI responsive molecular signatures to other tissues. Moreover, various TBI-associated diseases were identified as preferentially affected using a gene network approach, indicating that the hair follicle may be capable of reflecting comprehensive responses to TBI conditions. Accordingly, the present study demonstrates that the hair follicle is a potentially viable system for rapid and non-invasive TBI diagnosis.</p></div

Inflammatory responses enriched by GO term analysis.

<p>Red indicates that the gene is increased and green indicates that the gene is decreased in mRNA levels.</p

Rat chromosome 13p13 is a significantly enriched chromosomal position.

<p>The region has an overall decrease of −1.39-fold. Genes are shown in their position relative to the other genes from position 7,714,565 to 17,020,846. Red indicates the gene in increased in mRNA abundance in the hair follicle while green indicates that the gene is decreased in mRNA abundance.</p

Pathways and biological processes enriched in SNEA analysis in rat hair follicles upon blast exposure.

<p>Pathways and biological processes enriched in SNEA analysis in rat hair follicles upon blast exposure.</p

Chromosome enrichment identified regions of the rat genome that contain groups of genes that preferentially increased or decreased in mRNA levels in the hair follicle.

<p>Chromosome enrichment identified regions of the rat genome that contain groups of genes that preferentially increased or decreased in mRNA levels in the hair follicle.</p