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Long Term Research Goals

My long term goals are to understand the relationship between protein misfolding/aggregation and its role in the disease process. We are applying unique biochemical and biophysical approaches (including novel fluorescent molecules) to study consequences of protein misfolding in vitro and how it relates to misfolding in vivo, and the role molecular crowding plays in the process. Research in my lab focuses on analysis of biochemical and biophysical properties including stability and post-translational modifications of proteins involved in neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS), Alzheimerís disease (AD), Parkinsonís disease (PD), prion diseases, and Huntingtonís disease (HD), which misfold and show intracellular or extracellular aggregates at the end stage of the disease. Characterization of unique properties of the mutant proteins or WT protein exposed to extremes of pH and conditions mimicking cellular stresses (e.g. reducing environment, oxidative changes) will lead to a better understanding of how protein misfolding and aggregation affect the overall health of a cell. In my research experience, I have continued to use variety of biochemical and biophysical techniques such as UV-visible spectroscopy, fluorescence, differential scanning calorimetry, isothermal titration calorimetry, mass spectrometry, electrophoresis, chromatography, western blotting, scanning electron microscopy and fluorescence microscopy to answer specific scientific questions. My research work has demonstrated that aberrant hydrophobicity of SOD1 proteins may be key to their toxicity. While we understand that hydrophobicity of proteins is central to many protein aggregation diseases, identifying these aberrantly exposed areas on protein surface is a very challenging task. To address this issue my lab is working on developing novel fluorescent probes in collaboration with Dr. Liu that will be used to characterize the aberrantly exposed hydrophobic surface of mutant SOD1s and other proteins. Furthermore, we plan to use these novel fluorescent probes to monitor the aggregation and localization of aggregated proteins in neuronal and non-neuronal (mammalian) cell lines by linking the probes to specific targeting sequences and follow their path using fluorescence and confocal microscopy. This platform will allow us to study the consequences of protein misfolding both in vitro and in vivo , and the role molecular crowding plays in the process. Such studies will help us identify the nature of misfolded proteins, their preferred cellular localization, their aberrantly exposed surface, and interacting partner(s), and hence provide target(s) for novel therapeutic avenues.

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© Copyright 2011 Ashutosh Tiwari