Author ORCID Identifier
https://orcid.org/0000-0002-1750-928X
Date of Graduation
6-2024
Document Type
Dissertation (PhD)
Program Affiliation
Immunology
Degree Name
Doctor of Philosophy (PhD)
Advisor/Committee Chair
Dr. Louise D. McCullough, M.D., Ph.D.
Committee Member
Dr. Jennifer A. Wargo, M.D.
Committee Member
Dr. Pamela L. Wenzel, Ph.D.
Committee Member
Dr. Antonio L. Teixeira, M.D., Ph.D.
Committee Member
Dr. Juneyoung Lee, Ph.D.
Committee Member
Dr. Huihui Fan, M.D., Ph.D.
Abstract
MicroRNAs play a crucial role in multiple biological processes, including development, cell differentiation, proliferation, metabolism, and cell death. Aberrant regulation of microRNAs is seen in many diseases, such as sepsis, cardiovascular disease, neurological diseases such as stroke, and metabolic disorders. Because of their involvement in disease processes, microRNAs have been investigated as both potential biomarkers, and as therapeutic targets. Age-related inflammatory diseases including diabetes, obesity, and atherosclerosis are important risk factors for infection and sepsis. Intestinal barrier impairment occurs with aging and after brain injuries, including stroke. Both aging and stroke increase the risk of infection and sepsis and are a common cause of death in stroke patients. There has been a paucity of research examining the impact of microRNAs on stroke-induced sepsis, specifically regarding their involvement in regulating intestinal barrier integrity. In a mouse model of sepsis generated via cecal ligation and puncture, we found altered microRNA profiles in intestinal epithelial cells that functionally regulate and shape the IEC-specific transcriptome. We found increased expression of 14 microRNAs, and a decrease in the expression of 9 microRNAs in intestinal epithelial cell with sepsis. The expression of several microRNAs, such as miR-149-5p, miR-466q, miR-495, and miR-511-3p, was increased with disrupted intestinal barriers, and IECs of septic mice regulated Wnt signaling in pathway analysis. Some of these altered miRNAs were noted to be key drivers of oxidative stress, apoptosis, and ischemia which may explain the heightened risk of sepsis in stroke patients. Collectively, it is evident that systemic inflammation is a contributing factor for the development of infection and sepsis.
In conclusion, social isolation exacerbates stroke outcomes, and alters microRNA expression profiles, suggesting a potential interplay between social factors, inflammation, microRNA regulation, and microglial activation in stroke pathology. Understanding these intricate connections could offer insights into novel therapeutic targets for effective stroke management. Future studies investigating microglial-specific miRNAs in the context of post-stroke social isolation and how they exacerbate pro-inflammatory cytokine activation and cognitive impairment are warranted.
Keywords
Social Isolation, Stroke, Sepsis, Peripheral Inflammation, Microglial Activation, Metabolic Dysfunction
Included in
Immunity Commons, Molecular and Cellular Neuroscience Commons, Other Social and Behavioral Sciences Commons