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.

National Institute of Health (NIH)
National Eye Institute (NEI)
Research Project--Cooperative Agreements (U01)
Project #
Application #
Study Section
Special Emphasis Panel (ZEY1-VSN (05))
Program Officer
Neuhold, Lisa
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Case Western Reserve University
Schools of Medicine
United States
Zip Code
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
Mustafi, Debarshi; Kevany, Brian M; Bai, Xiaodong et al. (2016) Transcriptome analysis reveals rod/cone photoreceptor specific signatures across mammalian retinas. Hum Mol Genet 25:4376-4388
Mustafi, Debarshi; Kevany, Brian M; Bai, Xiaodong et al. (2016) Transcriptome analysis reveals rod/cone photoreceptor specific signatures across mammalian retinas. Hum Mol Genet :
Palczewska, Grazyna; Maeda, Akiko; Golczak, Marcin et al. (2016) Receptor MER Tyrosine Kinase Proto-oncogene (MERTK) Is Not Required for Transfer of Bis-retinoids to the Retinal Pigmented Epithelium. J Biol Chem 291:26937-26949

Showing the most recent 10 out of 18 publications