Our overall goals are to develop new optogenetic tools, which sensitize to light the activity of signaling proteins and the cells in which they are expressed. We will employ these remote controls for basic research into understanding and manipulating the mast cell secretion in response to antigens and allergens (which trigger the inflammatory response), fluid absorption across the retinal pigment epithelium (which plays a role in cystoid macular edema), as well as efforts to re-engineer neurons for cell replacement therapy for models of CNS neurodegeneration. We have already made significant progress in two other directions, which represent our major preclinical work, namely efforts toward: a) the treatment of pain and the analysis of pain circuits, and b) the restoration of vision in retinal pathologies that lead to loss of photoreceptors and blindness. Our approach is to develop molecularly focused methods for dynamic manipulation of specific proteins in the complex environment of cells, which can be used in intact tissues, and, indeed, in the live animal. The logic is to use light as both input and output to probe and control protein function in cells. While there has been significant progress in optical detection of protein function over the last 2 decades, remote control has become only possible recently, partly from the efforts of our NDC. The NDC for the Optical Control of Biological Function has spent the first funding period developing methods for using light to rapidly switch on and off the function of select proteins in cells. We have demonstrated that the strategies are broadly applicable across protein classes, including ion channels, G-protein coupled receptors and enzymes: three of the largest families of signaling proteins in cells and major drug targets for the development of new pharmaceuticals.

Public Health Relevance

The aim of the NDC initiative has been to use the tools of nanoscience to develop new approaches to the treatment of human disease. We have developed nanoscopic chemical photoswitches that enable the remote control ofthe function of signaling proteins in cells using light. We apply these to the restoration of vision to animal models of blinding diseases that lead to loss ofthe photoreceptor cells ofthe retina and to the treatment of pain.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Development Center (PN2)
Project #
5PN2EY018241-07
Application #
8146934
Study Section
Special Emphasis Panel (ZEY1-VSN (20))
Program Officer
Fisher, Richard S
Project Start
2006-09-30
Project End
2015-07-31
Budget Start
2011-08-01
Budget End
2012-07-31
Support Year
7
Fiscal Year
2011
Total Cost
$5,000,000
Indirect Cost
Name
University of California Berkeley
Department
Biology
Type
Other Domestic Higher Education
DUNS #
124726725
City
Berkeley
State
CA
Country
United States
Zip Code
94704
Kienzler, Michael A; Isacoff, Ehud Y (2017) Precise modulation of neuronal activity with synthetic photoswitchable ligands. Curr Opin Neurobiol 45:202-209
Berry, Michael H; Holt, Amy; Levitz, Joshua et al. (2017) Restoration of patterned vision with an engineered photoactivatable G protein-coupled receptor. Nat Commun 8:1862
Newman, Zachary L; Hoagland, Adam; Aghi, Krishan et al. (2017) Input-Specific Plasticity and Homeostasis at the Drosophila Larval Neuromuscular Junction. Neuron 93:1388-1404.e10
Palty, Raz; Fu, Zhu; Isacoff, Ehud Y (2017) Sequential Steps of CRAC Channel Activation. Cell Rep 19:1929-1939
Pantoja, Carlos; Hoagland, Adam; Carroll, Elizabeth et al. (2017) Measuring Behavioral Individuality in the Acoustic Startle Behavior in Zebrafish. Bio Protoc 7:
Levitz, Joshua; Broichhagen, Johannes; Leippe, Philipp et al. (2017) Dual optical control and mechanistic insights into photoswitchable group II and III metabotropic glutamate receptors. Proc Natl Acad Sci U S A 114:E3546-E3554
Levitz, Joshua; Habrian, Chris; Bharill, Shashank et al. (2016) Mechanism of Assembly and Cooperativity of Homomeric and Heteromeric Metabotropic Glutamate Receptors. Neuron 92:143-159
Tochitsky, Ivan; Helft, Zachary; Meseguer, Victor et al. (2016) How Azobenzene Photoswitches Restore Visual Responses to the Blind Retina. Neuron 92:100-113
Berlin, Shai; Szobota, Stephanie; Reiner, Andreas et al. (2016) A family of photoswitchable NMDA receptors. Elife 5:
Downs, Louise M; Scott, Erin M; Cideciyan, Artur V et al. (2016) Overlap of abnormal photoreceptor development and progressive degeneration in Leber congenital amaurosis caused by NPHP5 mutation. Hum Mol Genet 25:4211-4226

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