Advisory Committee Chair
Adam Wende
Document Type
Dissertation
Date of Award
2024
Degree Name by School
Doctor of Philosophy (PhD) Heersink School of Medicine
Abstract
Much modern biomedical research is invested in determining causative molecular mechanisms and identifying potential therapeutics within human disease or injury. Traditional experiments such as over-expressing or “knocking out” the level of a gene’s abundance can determine the specific contribution of a single gene to a pathology and are a vital component of scientific research. However, taking a big picture approach through the application of ‘omics technologies can lead to a broader overall understanding of a pathology and can potentially generate numerous specific hypotheses to be tested using the more traditional molecular approaches. In this dissertation, transcriptomic and epigenomic technologies, measuring gene expression and DNA methylation (DNAm), respectively, were applied to multiple pathologies to identify important patterns of changes and potential key drivers of the pathologies. These included 1) type II diabetes (T2D), a metabolic disorder characterized by high blood glucose and increased risks for comorbidities such as cardiovascular disease, 2) heart failure (HF), a high mortality form of cardiovascular disease where the heart is unable to pump sufficient blood throughout the body, and 3) skeletal muscle atrophy, a phenomenon that occurs with muscle disuse, specifically pathologies such as spinal cord injury (SCI), whereby the muscle drastically weakens and loses mass. Within the three studies presented here, we found 1) cardiac transcriptional remodeling by T2D which implicated increases in fibrosis, as well as elevated cardiac inflammation specifically in T2D HF patients, 2) DNAm and gene expression-based evidence for altered transcription factor binding and activity by T2D within end-stage HF patients as well as race-specific patterns within a subset of these changes including differing immune signaling, and 3) widescale transcriptomic changes and modest DNAm alterations within paralyzed mouse skeletal muscle following SCI which associated with atrophy, denervation, and neuromuscular junction remodeling related pathways. These studies highlight the power of ‘omics methodologies, both individually and through multiomic integration, to decipher the molecular underpinnings of diverse pathologies. Overall, this dissertation contributes to a stronger understanding of disease pathology and lays the groundwork for development of targeted therapeutics and the overall advancement of precision medicine across multiple health conditions.
Recommended Citation
Potter, Luke, "Unmasking Molecular Mechanisms Of Multiple Maladies Through Multiomic Methodologies" (2024). All ETDs from UAB. 3874.
https://digitalcommons.library.uab.edu/etd-collection/3874