Official websites use .gov

A .gov website belongs to an official government organization in the United States.

Secure .gov websites use HTTPS

A lock ( 🔒 ) or https:// means you've safely connected to the .gov website. Share sensitive information only on official, secure websites.

Need Help

ROLE OF ARACHIDONIC ISOFORMS IN NERVE CELL FUNCTION

Award Number: R21NS057473
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/01/2007
PERIOD OF PERFORMANCE END DATE: 06/30/2009

Group Awards By:

View Award Description

ROLE OF ARACHIDONIC ISOFORMS IN NERVE CELL FUNCTION - DESCRIPTION (provided by applicant): Inappropriate electrical activity gives rise to devastating brain disorders including, epilepsies and cell death following ischemia. These diseases trigger damaging inflammatory responses that elevate free arachidonic acid (AA) levels. Under these pathological conditions, excessive Ca2+ influx leads to cell death. By understanding the role that AA serves in modulating nerve cell excitability and survival, we hope to identify therapeutic targets that will minimize nerve cell death due to inflammatory signaling. My lab has found that AA inhibits two Ca2+ currents called L- and N-currents in superior cervical ganglion (SCG) neurons by promoting channel closing. AA also increases N-current amplitude by acting at a distinct site. As with inhibition, enhancement is mimicked by stimulating M1 muscarinic receptors and requires phospholipase A2, indicating functional relevance of AA's dual actions. We have measured increased AA release from individual SCG following muscarinic stimulation using gas chromatography (GC) and mass spectroscopy (MS). Three additional, distinct peaks with a mass/charge ratio (m/z) equal to that of AA are also released suggesting that SCGs acutely synthesize AA isoforms with novel double bond patterns. AA normally has four cis double bonds. Our findings appear to be the first study documenting AA isoforms in neurons. However a recent report described a peroxidation process in endothelial cells that generates AAs with one of the bonds in the trans- conformation (TAAs). Moreover TTAs appear to mediate oxidative stress-induced microvascular degeneration. These findings raise many questions surrounding the roles of AA versus its isoforms in normal and pathological nerve cell functioning. Because of the possible clinical relevance of AA isoforms as therapeutic targets for the treatment of ischemia, the following specific aims are proposed: Aim I. Define the chemical structures of the AA isoforms released from SCG using GC-MS and nanospray ionization MS-MS. Characterizing the changes in AA double bond geometry and/or location will allow us to identify new potential proinflammatory signaling molecules. Aim II. Separate, collect and test the four AA isoforms found in SCG neurons for their ability to modulate whole-cell Ca2+ currents of SCG neurons and recombinant channels transiently transfected into HEK293 cells. Aim III. Determine whether any of the AA isoforms alter action potential firing. Whether particular AA isoforms promote nerve cell growth or death will also be tested. These studies will document at the cellular level the cumulative effect of AA (or AA isoforms) on membrane excitability and viability. If one or more of the isoforms modulates channel activity, action potential firing and/or cell survival, we will have identified a new signaling molecule(s) that may serve as a novel therapeutic target for treating ischemia. Inappropriate electrical activity gives rise to devastating brain disorders including, epilepsies and cell death following ischemia. These diseases trigger damaging inflammatory responses that elevate free arachidonic acid (AA) levels. We have discovered what appear to be novel isoforms of AA in a peripheral ganglion that regulates blood flow to the brain. By understanding the roles that AA and the novel AA isoforms serve in modulating nerve cell excitability, growth and survival, we hope to identify therapeutic targets that will minimize nerve cell death due to inflammatory signaling. Public Health Relevance: This Public Health Relevance is not available.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2008 ( Subtotal = $177,734 )
2008	2008	UNIVERSITY OF MASSACHUSETTS	STATE HOUSE ROOM 109	BOSTON	MA	02133	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	6/13/2008	NON-COMPETING CONTINUATION	$177,734
														Subtotal = $177,734

Issue Date FY: 2007 ( Subtotal = $213,281 )
2007	2007	UNIVERSITY OF MASSACHUSETTS	STATE HOUSE ROOM 109	BOSTON	MA	02133	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	5/11/2007	NEW	$213,281
														Subtotal = $213,281

Grand Total All Awards = $391,015

Top

All Categories

About

Search

Reports

Data Submission

Award Information

ROLE OF ARACHIDONIC ISOFORMS IN NERVE CELL FUNCTION

Award Number: R21NS057473

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 07/01/2007

PERIOD OF PERFORMANCE END DATE: 06/30/2009

Federal Websites

Department of Health & Human Services

HHS Operating Divisions

HHS Staff Divisions

Download A Document Viewer