Date of Award
January 2025
Document Type
Dissertation
Degree Name
Doctor of Philosophy (PhD)
Department
Biomedical Engineering
First Advisor
Junguk Hur
Second Advisor
Ramkumar Mathur
Abstract
Neurodegenerative diseases, including Amyotrophic Lateral Sclerosis (ALS) and Alzheimer’s disease (AD), are characterized by progressive neuronal loss and functional decline, driven by chronic neuroinflammation and oxidative stress. ALS primarily affects motor neurons, leading to muscle weakness and paralysis, while AD results in cognitive decline due to widespread neuronal degeneration. Microglia, the brain’s resident immune cells, maintain neuronal health but can become excessively reactive under mitochondrial dysfunction, exacerbating neuroinflammatory responses. Mitochondrial Transcription Factor A (TFAM), essential for mitochondrial DNA (mtDNA) stability and function, is critical for mitochondrial maintenance. Its dysfunction in microglia leads to impaired mitochondrial function, excessive reactive oxygen species (ROS) production, oxidative stress, and inflammatory signaling, all of which contribute to disease progression. However, the molecular mechanisms linking TFAM dysfunction to neuroinflammation remain poorly understood. This dissertation investigates these mechanisms using genetically engineered mouse models with microglial-specific TFAM deletion (Cre-loxP system) to mimic mitochondrial dysfunction. Single-cell RNA sequencing, proteomics analysis, and ontology-driven gene interaction networks were leveraged to identify transcription factors, pathways, and gene interactions involved in oxidative stress and neuroinflammation. Experimental validation using immunohistochemistry and quantitative PCR (qPCR) further assessed mitochondrial integrity and microglial activation. This study aims to uncover novel molecular interactions linking TFAM loss to mitochondrial damage and neuroinflammatory signaling, providing insights into potential therapeutic targets. By integrating computational and experimental approaches, this research advances the understanding of mitochondrial dysfunction and neuroinflammation, offering new strategies to mitigate oxidative stress and reduceinflammation.
Recommended Citation
Bansal, Benu, "A Computational And Experimental Framework For Investigating Mitochondrial Dysfunction In Neuroinflammation And Neurodegeneration" (2025). Theses and Dissertations. 7096.
https://commons.und.edu/theses/7096