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overview A major focus of the Dawson Lab is to better understand neurodegeneration and how to prevent or reverse childhood inherited lysosomal storage diseases. The 13 forms of Batten disease result from the failure to deliver, lysosomally degrade, or recycle brain proteins. We use a chemical biology approach to delivering enzymes across cell membranes by attaching a Histidine tag to the enzyme and binding it to the surface of solubilized fluorescent semi-conductor nanoparticles called Quantum dots (QDs). If we add a synthetic cell penetrating peptide, protein cargo is rapidly taken up by cells to replace lysosomal enzymes such as tripeptidylpeptidase 1, absent in the CLN2 form of Batten disease, in cell and mouse models of CLN2 Batten disease. We can design QDs to specifically target the enzyme to neurons or glia and can use a similar nanoparticle delivery system for both small molecule and gene silencing studies. When coupled to HPLC/mass-spectrometric analysis of lipids, we can also study the role of sphingolipids such as ceramides in reversing non-genetic diseases such as cancer and stroke. These sphingolipids promote cell death and drug resistance so we can target the enzymes, such as ceramide glucosyltransferase, by coupling gene silencing RNAs to our QD complexes.

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  • Sphingolipids