This project seeks to develop a novel gene transfer-based approach as an alternative to deep brain stimulation (DBS) in the treatment of advanced Parkinson's disease (PD). Viral gene transfer will be used to manipulate neuronal activity in basal ganglia structures. The underlying mechanism of DBS has not been clarified; the current hypotheses suggest either activation or inhibition of the brain regions targeted by high-frequency stimulation. The project employs an emerging technique to inhibit electrical activity in mammalian neurons by expressing a modified glutamate-gated chloride channel (GluCl) from C. elegans. Channel activation by ivermectin, an FDA-approved, a widely used anthelmintic, elicits a chloride conductance, clamping these neurons to the Nernst potential for chloride, thereby inhibiting action potentials ('silencing'). For this study the GluCl channel will be modified to convert it into a Na and K-selective, excitatory channel (""""""""GluNa""""""""). Adeno-associated and lentivirus vectors will be developed that encode both GluCl and GluNa. Thus, tools will be developed to stimulate or to inhibit neuronal activity. Injection of virus encoding either GluCl or GluNa channel into the subthalamic nucleus or substantia nigra pars reticulata will (1) provide a minimally invasive, adjustable approach to accomplish pharmacological DBS based on an FDA-approved drug, and (2) will generate further insights into the underlying mechanism of DBS.
Aim 1 will provide a cation-selective channel.
Aim 2 and 3 will test applicability of GluCl and GluNa (respectively) in the approach to pharmacological DBS.
Both aims will give insights into the mechanism of DBS. to public health If successful, the project will establish a new treatment option for Parkinson's disease and could also be used in other applications where deep brain stimulation is now being tested. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21EY018502-01
Application #
7330288
Study Section
Special Emphasis Panel (ZRG1-GGG-S (52))
Program Officer
Oberdorfer, Michael
Project Start
2007-09-30
Project End
2009-08-31
Budget Start
2007-09-30
Budget End
2008-08-31
Support Year
1
Fiscal Year
2007
Total Cost
$243,000
Indirect Cost
Name
California Institute of Technology
Department
Type
Schools of Arts and Sciences
DUNS #
009584210
City
Pasadena
State
CA
Country
United States
Zip Code
91125
Srinivasan, Rahul; Henderson, Brandon J; Lester, Henry A et al. (2014) Pharmacological chaperoning of nAChRs: a therapeutic target for Parkinson's disease. Pharmacol Res 83:20-9
Nichols, Weston A; Henderson, Brandon J; Yu, Caroline et al. (2014) Lynx1 shifts ?4?2 nicotinic receptor subunit stoichiometry by affecting assembly in the endoplasmic reticulum. J Biol Chem 289:31423-32
Frazier, Shawnalea J; Cohen, Bruce N; Lester, Henry A (2013) An engineered glutamate-gated chloride (GluCl) channel for sensitive, consistent neuronal silencing by ivermectin. J Biol Chem 288:21029-42