Thursday, November 21, 2024
11/21/2024
DESCRIPTION (provided by applicant): Acute kidney injury (AKI) affects more than 10 million people worldwide each year with reported mortalities from 15 to 60% in different patient populations. However, methods are lacking to support the early diagnosis of AKI that could lead to early intervention, improved therapy, better prognosis, and lower medical costs. For these reasons, the development of early diagnosis tools for AKI is one of the solicited research topics listed by the NIDDK. Our ultimate goal is to develop a portable device for reliable early detection of AKI at point of care. The innovation of our proposal lies in the combination of aptamer technology with microcantilever detection of serum/urine neutrophil gelatinase-associated lipocalin (NGAL), an early marker of AKI [2-4 hours at the onset of AKI with cutoff concentration of ~ 150 ng/ml (6.8 nM)]. Aptamers are ssDNAs/RNAs that bind their targets avidly and specifically, and are selected in vitro by Systematic Evolution of Ligands by EXponential enrichment (SELEX). For biosensor development, aptamers have many advantages over antibodies, including their smaller size, amenability to chemical synthesis and modifications and adaptability to a broad range of assay formats including a microcantilever detection system. A microcantilever is a beam, often of silicon, that is 1-5 ¿m thick and 500-100 ¿m long and anchored only at one end. The microcantilever bends when its surface stress changes due to the conformation change that occurs upon ligand-receptor (e.g. aptamer-target) interaction on its surface. The differential surface stress between a reference cantilever coated with a scrambled nucleic acid that does not bind the analyte and a sensing cantilever coated with an aptamer that binds the analyte is measured by interferometry. In this phase I study, we propose two specific aims: 1. Identify 2'F-modified aptamers that bind NGAL specifically with nanomolar affinity. 2. Demonstrate an aptamer-functionalized microcantilever device for NGAL detection. In phase I, we expect to develop a prototype of an aptamer-functionalized microcantilever that will be responsive to NGAL, which will be further optimized in phase II for reliable performance with serum and urine samples with robust signal/noise ratio, sensitivity, detection limit and dynamic range of measurement and that can be used at point of care to monitor for AKI.
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