Historically, unfractionated heparin has been used in the treatment and prevention of thromboembolic disorders. However, due to complications associated with heparin (such as bleeding), low molecular weight heparins (LMWHs) have been developed and are being used in place of unfractionated heparin. LMWHs have proven effective as antithrombotic agents; however, the effects of LMWHs cannot be readily reversed while unfractionated heparin can be reversed by protamine sulfate. The overall goal of this proposal is to develop an antithrombin (ATIII)-specific RNA aptamer that will combine the safely and efficacy of LMWH with the reversibility of unfractionated heparin. To accomplish this goal, an oligonucleotide antidote for this aptamer that will be used to rapidly reverse the anticoagulant properties of the aptamer will be developed. Proof of this concept is established by the development of an RNA aptamer and RNA aptamer antidote directed against coagulation factor Xa. In collaboration with this group, an antidote-controlled ATIII-specific RNA aptamer will be developed. This aptamer will mimic the action of LMWH by binding to the D-helix of ATIII and enhance ATIII inhibition of factor Xa. This aptamer/antidote pair will have advantages over LMWHs because it will not only be able to control thrombosis similar to LMWHs but the availability of an antidote will allow for better therapeutic regulation and intervention. The experiments proposed in this proposal will characterize this family of antithrombin-specific RNA aptamers using both in vitro and in vivo approaches.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
5F32HL076108-02
Application #
6844326
Study Section
Special Emphasis Panel (ZRG1-F10 (20))
Program Officer
Mondoro, Traci
Project Start
2004-01-01
Project End
2006-12-31
Budget Start
2005-01-01
Budget End
2005-12-31
Support Year
2
Fiscal Year
2005
Total Cost
$49,928
Indirect Cost
Name
University of North Carolina Chapel Hill
Department
Pathology
Type
Schools of Medicine
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
Morrow, Jarrett D; Cho, Michael H; Platig, John et al. (2018) Ensemble genomic analysis in human lung tissue identifies novel genes for chronic obstructive pulmonary disease. Hum Genomics 12:1
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Morrow, Jarrett D; Zhou, Xiaobo; Lao, Taotao et al. (2017) Functional interactors of three genome-wide association study genes are differentially expressed in severe chronic obstructive pulmonary disease lung tissue. Sci Rep 7:44232
Dodd, James W; Novotny, Paul; Sciurba, Frank C et al. (2015) Executive Function, Survival, and Hospitalization in Chronic Obstructive Pulmonary Disease. A Longitudinal Analysis of the National Emphysema Treatment Trial (NETT). Ann Am Thorac Soc 12:1473-81
Kaplan, Robert M; Sun, Qiankun; Ries, Andrew L (2015) Quality of well-being outcomes in the National Emphysema Treatment Trial. Chest 147:377-387
Cho, Michael H; McDonald, Merry-Lynn N; Zhou, Xiaobo et al. (2014) Risk loci for chronic obstructive pulmonary disease: a genome-wide association study and meta-analysis. Lancet Respir Med 2:214-25

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