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Fellowship in CNS Drug Discovery

Research Background

Dr. Taylor's research is directed to structures, re-cognition capacities, and regulation of expression of proteins governing neurotransmission in cholinergic synapses. His group cloned the first acetyl-cholinesterase (AChE) gene over 20 years ago. This was followed by analysis of its genomic DNA to delineate regulatory regions, the multiple splicing options and gene expression profiles in nerve and muscle. His studies of AChE structure and its complexes by crystallographic and fluorescence methods, characterizing a peripheral site on AChE and the demonstrating flexibility of the active center gorge, provided the basis for collaborative studies with Barry Sharpless' group employing freeze-frame, click chemistry. The very biological target itself (AChE) is used as the template in the synthesis of high affinity, selective inhibitors. Taylor's long standing work with nicotinic acetylcholine receptors (nAChR) defined ligand specificity in relation to state functions for receptor activation and desensitization and identified the structural determinants on nAChR governing ligand and peptide toxin specificity. More recently, his studies have been directed to the acetylcholine binding protein, a soluble surrogate of the receptor, whereby his group in collaboration with others, employed physical methods of fluorescence anisotropy decay, NMR, x-ray crystallography and deuterium hydrogen exchange to examine structure and selectivity of the ligand binding sites. Finally, through collaborative endeavors, Taylor's group uncovered much of what is known about the structure of neuroligin, a synaptic adhesion molecule homologous to AChE. Their structural studies on neuroligin have delineated alterations in processing and folding associated with congenital mutations found in the autism spectral disorders. These pathways suggest potential therapeutic modalities for this developmental condition.

Fellowship Program Objectives:

Research into structure-guided drug design with emphasis on the CNS.

Coursework and training on:

Dr. Taylor has taught in medical, graduate and pharmacy curricula for many years. He has written and edited premier textbooks in pharmacology, including Goodman & Gilman’s Pharmacological Basis of Therapeutics and Principles of Drug Action. His lectures have covered contemporary areas in pharmacokinetics, pharmacodynamics and pharmacogenomics.

Unique skills fellows will acquire during the program:

Dr. Taylor has trained many students and fellows now in industry and academia. Trainees will acquire unique insights into molecular recognition and drug action through Dr. Taylor and his collaborators.

Time allocation: Two years

The time devoted to discovery and clinical will be divided to complement the previous experiences of the candidate and accomplish the goals of the fellowship. Over the two-year training period, the fellow will spend 18 months at UCSD and 6 months in the industry setting.