Show simple item record

dc.contributor.authorPerry, Justin Bradleyen_US
dc.date.accessioned2020-10-17T06:00:34Z
dc.date.available2020-10-17T06:00:34Z
dc.date.issued2019-04-25
dc.identifier.othervt_gsexam:19559en_US
dc.identifier.urihttp://hdl.handle.net/10919/100602
dc.description.abstractDysfunction within complex I (CI) of the mitochondrial electron transport system has been implicated in a number of disease states ranging from cardiovascular diseases to neuro-ophthalmic indications. Herein, we provide three novel approaches to model and study the impacts of injury on the function of CI. Cardiovascular ischemia/reperfusion (I/R) injury has long been recognized as a leading contributor to CI dysfunction. Aside from the physical injury that occurs in the tissue during the ischemic period, the production of high levels of reactive oxygen species (ROS) upon reperfusion, led by reverse electron transport (RET) from CI, causes significant damage to the cell. With over 700,000 people in the US set to experience an ischemic cardiac event annually, the need for a pharmacological intervention is paramount. Unfortunately, current pharmacological approaches to treat I/R related injury are limited and the ones that have shown efficacy have often done so with mixed results. Among the current approaches to treat I/R injury antioxidants have shown some promise to help preserve mitochondrial function and assuage tissue death. The studies described herein have provided new, more physiologically matched, methods for assessing the impact of potential therapeutic interventions in I/R injury. With these methods we evaluated the efficacy of the coenzyme-Q derivative idebenone, a proposed antioxidant. Surprisingly, in both chemically induced models of I/R and I/R in the intact heart, we see no antioxidant-based mechanism for rescue. The mechanistic insight we gained from these models of I/R injury directed us to further examine CI dysfunction in greater detail. Through the use of two cutting edge genetic engineering approaches, CRISPR/Cas9 and Artificial Site-specific RNA Endonucleases (ASRE), we have been able to directly edit the mitochondria to accurately model CI dysfunction in disease. The use of these genetic engineering technologies have provided first in class methods for modeling three unique mitochondrial diseases. The culmination of these projects has provided tremendous insight into the role of CI in disease and have taken a significant step towards elucidating potential therapeutic avenues for targeting decrements in mitochondrial function.en_US
dc.format.mediumETDen_US
dc.publisherVirginia Techen_US
dc.rightsThis item is protected by copyright and/or related rights. Some uses of this item may be deemed fair and permitted by law even without permission from the rights holder(s), or the rights holder(s) may have licensed the work for use under certain conditions. For other uses you need to obtain permission from the rights holder(s).en_US
dc.subjectMitochondriaen_US
dc.subjectIschemia/Reperfusionen_US
dc.subjectMitochondrial Diseaseen_US
dc.subjectGenome Editingen_US
dc.subjectIdebenoneen_US
dc.titleNovel approaches to treat mitochondrial complex-I mediated defects in diseaseen_US
dc.typeDissertationen_US
dc.contributor.departmentHuman Nutrition, Foods and Exerciseen_US
dc.description.degreeDoctor of Philosophyen_US
thesis.degree.nameDoctor of Philosophyen_US
thesis.degree.leveldoctoralen_US
thesis.degree.grantorVirginia Polytechnic Institute and State Universityen_US
thesis.degree.disciplineHuman Nutrition, Foods, and Exerciseen_US
dc.contributor.committeechairBrown, David A.en_US
dc.contributor.committeememberGrange, Robert W.en_US
dc.contributor.committeememberHulver, Matthew Wadeen_US
dc.contributor.committeememberAllen, Irving Coyen_US


Files in this item

Thumbnail

This item appears in the following Collection(s)

Show simple item record