Identification of Genetic Variants Influencing Efficacy of Lisinopril Treatment on Age-specific Physical Performance: A Genome-wide Analysis in Drosophila melanogaster
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Date
2018-01-01
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Department
Biological Sciences
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Biological Sciences
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Access limited to the UMBC community. Item may possibly be obtained via Interlibrary Loan thorugh a local library, pending author/copyright holder's permission.
This item is likely protected under Title 17 of the U.S. Copyright Law. Unless on a Creative Commons license, for uses protected by Copyright Law, contact the copyright holder or the author.
Abstract
Age-related decline in physical performance is a general phenomenon in most organisms and in humans confers high risk for disability and mortality. Despite the near ubiquity of senescence and extensive variation among individuals in age-related decline in physical performance, we know little about the genes responsible for this variation. In humans, alterations in the Renin-Angiotensin System (RAS) have been implicated in the pathogenesis of late life physical decline. Pharmacological blockade of RAS, such as that by angiotensin-converting enzyme inhibitor Lisinopril, has been proposed as a treatment to attenuate such age-related declines. Some studies have shown effectiveness of these drugs for treatment of late-age declines while others have failed to show any effect. Conflicting results between studies can potentially be explained by genetic differences among individuals. The primary goal of this research was to develop methods to measure physical performance with age and identify, via genome-wide association (GWA) and follow-up functional genetic studies, genes associated with physical ability at late age and those that contribute to differences among genotypes in the phenotypic response (climbing speed and endurance) to Lisinopril. I used Drosophila melanogaster as a model system and the Drosophila Genetic Reference Panel (DGRP) for GWA mapping. The second goal was to map climbing speed and endurance in untreated and Lisinopril-treated flies. This revealed genetic pathways that are acted on by this drug and polymorphisms that altered individual responses to the drug. My results have contributed to our understanding of the genetic bases of natural variation in physical performance at older ages. Many of the genes identified this study have human orthologs. As a result, my findings have laid the groundwork for designing personalized medical applications to treat age-related declines in physical performance and provide novel genetic targets for pharmaceutical development to extend health span in older adults.