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1. Development of targeted, photoactivatable probes

Small molecules have crucial biological functions, such as being the building blocks of macromolecules, providing energy to the cell, and serving as ligands that modulate enzymatic activity. These functions are largely defined by the subcellular localization of these molecules. To understand these effects, we are interested in developing molecular probes that can be used to perturb the concentration of selected molecules within the boundaries of a particular organelle. The creation of such probes will involve the synthesis of small organic molecules and peptides, mechanistic studies of targeting and activation reactions, and the implementation of the probes in live cells using fluorescence microscopy. The goal is to be able to probe the biological activity of selected small molecules in specific intracellular locales.

2. Fluorescent sensing of epigenetic modifications

When small molecules interact with enzymes that carry out posttranslational modifications of DNA and DNA-associated proteins (epigenetic modifications), the expression of proteins is altered beyond the instructions encoded in the primary sequence of DNA. Developing methods to detect the activity of such enzymes is therefore essential to understand the connection between small molecule metabolism and the epigenetic control of gene expression. Driven by modeling and synthesis, we will prepare libraries of fluorescent sensors with optimal photophysical properties, precise molecular recognition motifs, and carefully tailored sensing mechanisms to detect the activity of epigenetic enzymes and epigenetic marks on histones and DNA. The goal is to create robust small-molecule, membrane permeable optical probes that can be utilized in live cells to assess the activation of epigenetic modifications upon stimulation.

3. High-resolution imaging of signaling agents

The precise localization of small molecules and ions within cellular organelles cannot be resolved using diffraction-limited microscopies. This information, however, is necessary to understand how the accumulation of these analytes in particular locales affects their biological processes. Although many optical chemosensors are known, only very few are compatible with superresolution microscopy techniques. We will develop molecular probes that can detect signaling agents, such as small molecules and ions, and be imaged with single-molecule resolution. The development of these sensors will require the synthesis of probes and extensive mechanistic studies to characterize the interplay between sensing mechanisms and photophysical properties. The goal of this project is to be able to image, in real-time, signaling agents with sub-organelle resolution in live specimens.

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