项目来源

美国卫生和人类服务部基金(HHS)

项目主持人

KINDZELSKI, ANDREI L.

项目受资助机构

DUKE UNIVERSITY

立项年度

2018

立项时间

未公开

项目编号

5R01HL065222-17

项目级别

国家级

研究期限

未知 / 未知

受资助金额

465035.00美元

学科

Biotechnology; Cardiovascular; Clinical Research; Heart Disease; Heart Disease - Coronary Heart Disease; Hematology; Women's Health;

学科代码

未公开

基金类别

Non-SBIR/STTR RPGs

关键词

未公开

参与者

SULLENGER, BRUCE ALAN

参与机构

NATIONAL HEART, LUNG, AND BLOOD INSTITUTE

项目标书摘要：? DESCRIPTION (provided by applicant): Four interrelated but independent hypotheses are being tested in this proposal. A) Aptamers can serve as molecular probes to identify functionally important exosites on coagulation factor proteases, B) Exosite-binding aptamers that inhibit coagulation factors in the contact pathway can limit thrombosis without increasing bleeding, C) Combinations of two exosite-binding aptamers and combinations of an aptamer and small molecule active site inhibitor represent potent, yet rapidly reversible anticoagulation strategies that can support cardiopulmonary bypass surgery and D). The exosite binding Factor IX/IXa aptamer targeting a contact pathway factor will limit factor Xa and thrombin generation and inflammation more effectively than targeting common pathway factors in patients undergoing PCI. Each of these lines of investigation rationally build upon important results obtained in the current funding cycle of this award. Our specific aims are: Aim 1: To utilize aptamers to identify exosites on coagulation factors XIIa, XIa, IXa, Xa, VIIa and Kallikrein. Aim 2: To evaluate the ability of aptamers targeting exosites on contact pathway factors to act as potent yet safe antithrombotic agents. Aim 3: To elucidate the mechanism by which combinations of A) aptamer-based inhibitors and B) aptamer-based exosite and active site inhibitors of Factor Xa and thrombin synergize and determine if such combinations can produce rapid and safe anticoagulation for cardiopulmonary bypass (CPB) and if antidotes can produce rapid and safe neutralization of anticoagulation following discontinuation of CPB. Aim 4: To determine if our factor IXa aptamer limits thrombin and factor Xa generation more effectively than bivalirudin in ACS patients undergoing PCI and if this results in a reduction in inflammation in such patients.