Molecular Recognition & Biosensing
Research in the Miller group focuses on two fundamental areas: the control of biomolecular interactions through the synthesis of new small-molecule probes, and the observation of biomolecular interactions through the development of novel optical sensing technologies. In the area of control, we are particularly interested in the sequence-selective recognition of RNA. New RNA sequences with important functions in basic biology and human health and disease are being discovered at an ever-increasing rate, and yet our ability to target these sequences specifically is still at a rudimentary stage. To address this gap, we are applying techniques of molecular design and a novel combinatorial method of small-molecule evolution called Dynamic Combinatorial Chemistry, which allows us to rapidly
prototype sequence-selective RNA binding molecules. Thus far we have used this methodology to RNA targets important in Myotonic Dystrophy and HIV. Protein-targeted small-molecule discovery projects are also of interest, and current projects include the mechanism of tight junction formation and the transport of beta-amyloid across the blood-brain barrier.
To the end of achieving better methods of observing biomolecular interactions, our group has a longstanding program in the use of the optical properties of nanostructured materials as the basis for new biosensors and diagnostic tools. Two examples of current efforts include Arrayed Imaging Reflectometry (AIR) and sensors based on two-dimensional photonic crystals (2-D PhC). AIR relies on the creation of a near-perfect antireflection coating on the surface of a silicon chip; binding of a biomolecular target destroys this antireflective condition and is visible by a change in reflected light. This allows for highly multiplexed (10's to 1000's of targets) and quantitative detection. Photonic crystal sensors, on the other hand, offer the possibility of ultrasensitive detection: for example, a major long-term goal of our work is the production of sensors that can effectively detect one virus in a blood sample.
- Effects of multiple genetic Loci on age at onset in late-onset Alzheimer disease: a genome-wide association study. JAMA Neurol. 71, 1394-404. (2014 Nov 01).
- Dysfunctionally phosphorylated type 1 insulin receptor substrate in neural-derived blood exosomes of preclinical Alzheimer's disease. FASEB J. In press. (2014 Oct 23).
- Identification of activators of ERK5 transcriptional activity by high-throughput screening and the role of endothelial ERK5 in vasoprotective effects induced by statins and antimalarial agents. J Immunol. 193, 3803-15. (2014 Oct 01).