Author ORCID Identifier
Date Available
8-6-2023
Year of Publication
2023
Degree Name
Doctor of Philosophy (PhD)
Document Type
Doctoral Dissertation
College
Medicine
Department/School/Program
Pharmacology and Nutritional Sciences
First Advisor
Ryan E. Temel
Abstract
Atherosclerosis, characterized by lipid accumulation and arterial inflammation, is a major contributor to global morbidity and mortality. Despite significant progress in understanding atherosclerosis in extracranial arteries, the study of intracranial atherosclerosis (ICAS) has been relatively neglected, despite its crucial role in stroke and vascular cognitive impairment. Challenges related to ICAS, including its location within the cranium and limited availability of suitable animal models, have hindered research progress in this area. Although nonhuman primates (NHPs) are commonly used for studying extracranial atherosclerosis, a comprehensive understanding of ICAS pathophysiology in these animals is lacking. By subjecting NHPs to a high-fat/cholesterol diet, we successfully induced measurable ICAS, providing a unique opportunity to investigate underlying mechanisms and potential therapeutic strategies for ICAS regression. This study presents a robust NHP model of ICAS development and explores the potential of miR-33 antagonism for promoting atherosclerosis regression. Mouse studies have shown that inhibiting miR-33a can stabilize or regress atherosclerosis in extracranial arteries, but their translatability is limited. To address this, we employed an NHP model that closely mimics human miR-33a and miR-33b expression and atherosclerosis development. Our investigation aims to assess the effectiveness of miR-33 antagonism in promoting ICAS regression in 61 NHPs, using histological characterization and digital pathology techniques to evaluate ICAS morphology and composition. Surprisingly, our results showed no histological evidence supporting the efficacy of miR-33 antagonism in improving ICAS regression measures. This study significantly contributes to our understanding of ICAS and its potential treatment strategies by establishing a reliable animal model for ICAS development. However, further investigation is required to determine the role of miR-33 antagonism in atherosclerosis regression. These findings have important implications for future research and the development of therapeutic strategies to improve brain health and function while reducing the burden of ICAS on stroke and vascular cognitive impairment.
Digital Object Identifier (DOI)
https://doi.org/10.13023/etd.2023.347
Funding Information
This study was supported by:
National Institutes of Health R21 Targeting microRNA-33 to Reduce Intracranial Atherosclerosis and Other Hallmarks of Vascular Cognitive Impairment and Dementia (R21NS111979) from 2019-2022
National Institutes of Health training grant (T32) Training in Translational Research in Alzheimer’s and Related Dementias (TRIAD) (T32AG057461) from 2018-2020
National Institutes of Health training grant (T32) Pharmacology and Nutritional Sciences: Multidisciplinary Approaches for Metabolic Disease (T32DK007778) from 2017-2018
Recommended Citation
Hecker, Peter, "Exploring the Efficacy of miR-33 Antagonism in Promoting Regression of Intracranial Atherosclerosis in a Nonhuman Primate Model" (2023). Theses and Dissertations--Pharmacology and Nutritional Sciences. 52.
https://uknowledge.uky.edu/pharmacol_etds/52
Included in
Cardiovascular Diseases Commons, Cardiovascular System Commons, Nervous System Diseases Commons, Neurosciences Commons, Pathological Conditions, Signs and Symptoms Commons
