DOI

10.17077/etd.lg3z-ny9x

Document Type

Dissertation

Date of Degree

Fall 2018

Degree Name

PhD (Doctor of Philosophy)

Degree In

Molecular and Cell Biology

First Advisor

Giangrande, Paloma

First Committee Member

Dupuy, Adam

Second Committee Member

Musselman, Catherine

Third Committee Member

McNamara, James

Fourth Committee Member

Wilson, Mary

Abstract

Sepsis is among the most prevalent diagnosed critical illnesses in the United States today. Although advances have reduced the overall morbidity and mortality associated with this illness, the enormous number of deaths associated with it shows a need for improved diagnostic and therapeutic optionsgent. Our laboratory has utilized RNA based technologies to aid in the treatment of histone induced multiple organ dysfunction syndrome seen in sepsis.

Histones are proteins found in the nucleus of every cell in our body and have been shown to be released during sepsis. Such release induces damage to other cells, causing a feed forward cycle that results in organ failure and death. Several therapeutics have been utilized to neutralize histones but have shown considerable toxicity. This thesis describes the generation of single stranded RNA aptamers to bind and neutralize histone mediate damage without unwanted toxicity. We demonstrate that our aptamers selectively bind to histones but not serum proteins. In addition, we establish that our aptamers can neutralize all histone mediated cellular response in vitro and in vivo. Finally, we determined that our aptamers are able inhibit the histone feed forward cycle in a temporal fashion in our murine model of multiple organ dysfunction. This novel therapeutic demonstrates the selectivity and effectiveness needed to inhibit histones in several critical illnesses.

Keywords

Aptamers, Extracellular Histones, OLIGONUCLEOTIDES, Sepsis

Pages

xiii, 196 pages

Bibliography

Includes bibliographical references (pages 169-196).

Copyright

Copyright © 2018 Kevin Thomas Urak

Included in

Cell Biology Commons

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