Oxysterols, the oxygenated derivatives of cholesterol, have been identified for several decades, however, their roles in the physiology and pathological processes, particularly in nervous system, are largely unknown. Our previous study showed that the major cholesterol metabolite, cholestane-3?, 5?, 6?-triol (Triol), functions as an important endogenous neuroprotectant. Here, we hypothesize that blockade of acid-sensing ion channel (ASIC) 1a serves as a novel mechanism underlying its neuroprotective effect, based on the following arguments and preliminary data: (1) The concentration of Triol increases after ischemic preconditioning (IPC), which contributes to IPC mediated neuroprotection; (2) The activation of calcium permeable ASIC1a exacerbates ischemic injury, and that pharmacological blockade or knockout of ASIC1a produces a significant protection; (3) In brain ischemia, blockade of ASIC1a has a therapeutic time window of ~5h, which is close to that of Triol (> 4h); (4) Our preliminary data clearly demonstrated that Triol significantly inhibits ASIC1a currents as well as its surface expression, at a concentration that occurs during ischemic preconditioning; (5) The preliminary data suggest that the inhibition of ASIC is specific to Triol, as its precursor cholesterol has no effect on ASIC currents. To rigorously test the hypothesis that Triol functions as an endogenous neuroprotectant through blockade of ASIC1a, the following specific aims will be examined:
Aim 1. Determine the effect of Triol on ASIC current and calcium entry.
Aim 2. Determine the inhibitory effect of Triol on ASIC1a surface expression.
Aim 3. Determine whether the neuroprotection caused by Triol is mediated through inhibition of ASIC1a.
Aim 4. Study the structure-activity relationship, and identify the amino acids that mediate the inhibitory effect of Triol on ASIC1a.

Public Health Relevance

This study will examine whether the blockage of ASIC1a serves as a novel mechanism underlying the neuroprotective effect of the major cholesterol metabolite, cholestane-3?, 5?, 6?- triol. Success of this study will increase our understanding of the endogenous neuroprotective mechanism and provide important structure information and lead compound for the design and development of novel drugs for the treatment of ASIC1a related neurological disorders such as stroke, pain and amyotrophic lateral sclerosis (ALS), etc.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Continuance Award (SC3)
Project #
1SC3GM122593-01A1
Application #
9417506
Study Section
Special Emphasis Panel (ZGM1)
Program Officer
Krasnova, Irina N
Project Start
2018-02-06
Project End
2022-01-31
Budget Start
2018-02-06
Budget End
2019-01-31
Support Year
1
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Morehouse School of Medicine
Department
Neurosciences
Type
Schools of Medicine
DUNS #
102005451
City
Atlanta
State
GA
Country
United States
Zip Code
30310