One of the stated goals of the NEI Audacious Goal Initiative in addressing the technical needs and opportunities for imaging the visual system (U01) is to develop new technology for the non-invasive measurement of retina function in vivo as related to natural vision, including visualization of metabolism at the cellular level and electrical activities. Based on strong newly acquired preliminary data, this application proposes the development of a new instrument that can image the retina in exceptional detail that together with two highly sensitive related tests can be used to evaluate retinal function.
The specific aims are: (A) with a mouse two-photon ophthalmoscope (TPO), develop a novel diagnostic paradigm used to assess two functional aspects of vision: the metabolic flow of retinoids through the retinoid cycle and visual sensitivity. Along with mass spectrometric analyses, we will define critical intersections between images, structure, function and toxic molecules that affect the retina and identify potential therapies that preserve this neural tissue; and (B) develop and test a TPO imaging and diagnostic tool in humans. Initial tests will be done in a surrogate monkey/pig eye and then with the knowledge gained, we will image the eyes of individuals with advanced stages of blinding retinal diseases. Despite its' `audacity', this proposal can realistically be completed during the funding cycle. The scientific questions and interim milestones required to make this program successful are presented herein.

Public Health Relevance

Building on state-of-the-art technology and recent advances in biochemical/functional aspects of retinal vision, we propose to develop an advanced two-photon ophthalmoscope for repeated safe imaging of cells and tissues in the human retina. Together with novel measurements of retinal function, this unique diagnostic tool offers a major progress for the early detection and monitoring of treatment effectiveness for human blinding retinal diseases.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01EY025451-02
Application #
9059094
Study Section
Special Emphasis Panel (ZEY1)
Program Officer
Neuhold, Lisa
Project Start
2015-05-01
Project End
2020-04-30
Budget Start
2016-05-01
Budget End
2017-04-30
Support Year
2
Fiscal Year
2016
Total Cost
Indirect Cost
Name
Case Western Reserve University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
077758407
City
Cleveland
State
OH
Country
United States
Zip Code
44106
Palczewska, Grazyna; Stremplewski, Patrycjusz; Suh, Susie et al. (2018) Two-photon imaging of the mammalian retina with ultrafast pulsing laser. JCI Insight 3:
Daruwalla, Anahita; Choi, Elliot H; Palczewski, Krzysztof et al. (2018) Structural biology of 11-cis-retinaldehyde production in the classical visual cycle. Biochem J 475:3171-3188
Gao, Songqi; Parmar, Tanu; Palczewska, Grazyna et al. (2018) Protective Effect of a Locked Retinal Chromophore Analog against Light-Induced Retinal Degeneration. Mol Pharmacol 94:1132-1144
Sharma, Robin; Schwarz, Christina; Hunter, Jennifer J et al. (2017) Formation and Clearance of All-Trans-Retinol in Rods Investigated in the Living Primate Eye With Two-Photon Ophthalmoscopy. Invest Ophthalmol Vis Sci 58:604-613
Murashova, Gabrielle A; Mancuso, Christopher A; Sakami, Sanae et al. (2017) Epi-direction detected multimodal imaging of an unstained mouse retina with a Yb-fiber laser. Proc SPIE Int Soc Opt Eng 10069:
Hofmann, Lukas; Alexander, Nathan S; Sun, Wenyu et al. (2017) Hydrogen/Deuterium Exchange Mass Spectrometry of Human Green Opsin Reveals a Conserved Pro-Pro Motif in Extracellular Loop 2 of Monostable Visual G Protein-Coupled Receptors. Biochemistry 56:2338-2348
Murashova, Gabrielle A; Mancuso, Christopher A; Canfield, Jacob L et al. (2017) Multimodal nonlinear optical imaging of unstained retinas in the epi-direction with a sub-40 fs Yb-fiber laser. Biomed Opt Express 8:5228-5242
Kiser, Philip D; Palczewski, Krzysztof (2016) Retinoids and Retinal Diseases. Annu Rev Vis Sci 2:197-234
Alexander, Nathan S; Palczewska, Grazyna; Stremplewski, Patrycjusz et al. (2016) Image registration and averaging of low laser power two-photon fluorescence images of mouse retina. Biomed Opt Express 7:2671-91
Chen, Yu; Palczewska, Grazyna; Masuho, Ikuo et al. (2016) Synergistically acting agonists and antagonists of G protein-coupled receptors prevent photoreceptor cell degeneration. Sci Signal 9:ra74

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