The alkylphenol anesthetic propofol is used in millions of surgical and noxious procedures annually. While the clinical use of propofol has swelled, mechanistic understanding of its many actions, on all levels, has lagged behind. In this proposal, we will deploy our photoactive alkylphenol analogues of propofol, azi-propofol-m (aziPm) and 2-propynloxymethoxy-5-trifluoromethyldiazirinylphenol (aziPm-click), in a tiered series of studies to reveal: the photoactive alkylphenol binding proteome using state-of-the-art mass spectrometry and enrichment methods (aim 1), the electro- physiological character of photoactive alkylphenols in discrete nuclei in brain slices (aim 2), and the in-vivo contribution o individual cells and networks to the hypnotic effects of alkylphenols. These latter studies will us fiberoptic laser stimulation of discrete regions of brain in live mice after systemic administratio of photoactive alkylphenols (aim 3). The three aims are integrated by their common prediction of molecular substrates arising from very different, complimentary and unbiased approaches. These studies will result in the identification of novel and plausible molecular substrates for alkylphenol action, which will serve as the basis for validation in subsequent proposals involving the construction of genetically altered animals. This collaborative project is ideally suited to integrate the neurobiological expertise of the Kelz lab with the electrophysiologic mastery of the Beck lab, and the biological chemistry prowess of the Eckenhoff and Dailey labs.

Public Health Relevance

The injectable general anesthetics, typified by propofol, are being increasingly used in both surgery and noxious procedures, yet their mechanisms of action on all levels remain incompletely understood. We will deploy novel analogs of propofol, designed and synthesized in our labs, which can be activated by light to become exceptionally potent and durable, in a series of rationally tiered determinations of molecular, cellular and network substrates for this class of general anesthetic. This multidisciplinary campaign will result in knowledge that should allow development of anesthetics with an improved therapeutic ratio and side effect profile.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Surgery, Anesthesiology and Trauma Study Section (SAT)
Program Officer
Cole, Alison E
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University of Pennsylvania
Schools of Medicine
United States
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Woll, Kellie A; Zhou, Xiaojuan; Bhanu, Natarajan V et al. (2018) Identification of binding sites contributing to volatile anesthetic effects on GABA type A receptors. FASEB J 32:4172-4189
Woll, Kellie A; Skinner, Kenneth A; Gianti, Eleonora et al. (2017) Sites Contributing to TRPA1 Activation by the Anesthetic Propofol Identified by Photoaffinity Labeling. Biophys J 113:2168-2172
Wasilczuk, Andrzej Z; Proekt, Alexander; Kelz, Max B et al. (2016) High-density Electroencephalographic Acquisition in a Rodent Model Using Low-cost and Open-source Resources. J Vis Exp :
Woll, Kellie A; Murlidaran, Sruthi; Pinch, Benika J et al. (2016) A Novel Bifunctional Alkylphenol Anesthetic Allows Characterization of ?-Aminobutyric Acid, Type A (GABAA), Receptor Subunit Binding Selectivity in Synaptosomes. J Biol Chem 291:20473-86
Woll, Kellie A; Dailey, William P; Brannigan, Grace et al. (2016) Shedding Light on Anesthetic Mechanisms: Application of Photoaffinity Ligands. Anesth Analg 123:1253-1262
Erickson, Rebecca L; Terzi, Matthew C; Jaber, Samer M et al. (2016) Intraperitoneal Continuous-Rate Infusion for the Maintenance of Anesthesia in Laboratory Mice (Mus musculus). J Am Assoc Lab Anim Sci 55:548-57
Drobish, Julie K; Kelz, Max B; DiPuppo, Patricia M et al. (2015) Emergence delirium with transient associative agnosia and expressive aphasia reversed by flumazenil in a pediatric patient. A A Case Rep 4:148-50