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.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
1R01GM107117-01A1
Application #
8757721
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Program Officer
Cole, Alison E
Project Start
2014-08-01
Project End
2018-07-31
Budget Start
2014-08-01
Budget End
2015-07-31
Support Year
1
Fiscal Year
2014
Total Cost
$322,867
Indirect Cost
$121,075
Name
University of Pennsylvania
Department
Anesthesiology
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104