PROJECT SUMMARY
As the first step in vision, photoreceptors have the crucial role of transducing light into a neural signal. Therefore,
any dysfunction of photoreceptors through injury or disease is devastating to an individual’s vision. As a result,
photoreceptors are the target of numerous clinical and preclinical therapies, all aimed at restoring their function.
Unsurprisingly, preclinical and clinical trials place enormous value on outcome measures that can quickly reveal
positive (or negative) functional effects as quickly as possible. Despite a veritable explosion of preclinical
treatments, there is a relative dearth of cellular-scale non-invasive, in vivo functional assays for photoreceptors
in the preclinical domain. Here, we propose to develop non-invasive in vivo functional tools and techniques to
obtain and validate contrast-free functional signals from photoreceptors.
This study aims to: 1) Characterize the intensity-based optoretinogram from photoreceptors in vivo using
a tree shrew animal model, 2) Quantify and enhance the repeatability, reproducibility, and throughput of
functional imaging in the tree shrew, and 3) Validate the optoretinogram against “gold standard” measurements
of photoreceptor function in the tree shrew retina using mechanically and pharmacologically induced retinal
degenerations. We will address these goals by use of an animal-compatible adaptive optics scanning laser
ophthalmoscope, and the northern tree shrew animal model (Tupaia belangeri). We will first reverse-translate
the previously developed intensity-based optoretinogram from humans to the tree shrew. Next, we will establish
the minimum meaningful change that can be observed using an iORG in the tree shrew, assess inter-session
reproducibility, and develop tools to enhance efficient imaging in small animal models. Finally, we will utilize the
flexibility of the tree shrew animal model to investigate the ability of our nascent assays to sensitively measure
functional change in pharmacologically and mechanically induced retinal degenerations.
The expected outcomes of this work are to have established a valuable functional imaging technique in
the tree shrew that is capable of assessing functional change at the level of an individual cell, and to develop
imaging tools that are applicable to small animal imaging beyond the tree shrew. Ultimately, we expect these
outcomes to facilitate the translation of novel preclinical therapies to humans.