SampleNIHProposalreview - S ig n if ic a n c e : U n d e r...

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Significance: Understanding the subcellular localization of fluorescent drugs and their metabolites, how this localization is effected by mode of delivery and cellular machinery, and how localization affects drug action and toxicity is of high importance, although it is not clear how large of a group of drugs could be examined in this manner. For studies on nonfluorescent drugs, in which information on localization cannot be obtained, there is still reasonable value in seeking information on the subcellular effects of drug exposure. Approach: The proposal represents a resubmission of a proposal by a leading young bioanalytical chemist. Significant effort has been made to address concerns raised in the previous reviews, though the justification for microfluidics appears somewhat overstated. The Progress Report and Preliminary Work sections describe an impressive set of completed and on- going studies, indicating the PI is well positioned to make continued progress. However, some questions exist with data interpretation. For example, the initial metabolic profile results (Figure 9) are interesting, but don’t clearly support the assertion that MEKC can demonstrate differences in profiles between cell lines (certainly not in the case for Doxil; perhaps differences outside 1 σ are apparent for a few metabolites following solution treatment). The goal of Aim 1 is to increase speed of organelle measurements. Here, the advantage of switching to microfluidics may have been overstated. A six-fold decrease in analysis time is predicted (from 30 min with CE to 5 min with microfluidics); according to the data in Fig. 5, it appears CE can be accomplished in 10 min, and perhaps could be made even faster. The potential for parallelism of a microfluidics system could be advantageous, although it is not obvious how much experimenter input will be necessary to perform single-cell manipulations for each analysis channel; chip measurements of bulk preps would be (at least to some degree) limited by the preparation time. Of the justifications for single-cell measurements, the possibility of identifying cellular heterogeneities is the most compelling and
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This note was uploaded on 01/06/2012 for the course UGS 303 taught by Professor Foster during the Fall '08 term at University of Texas at Austin.

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SampleNIHProposalreview - S ig n if ic a n c e : U n d e r...

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