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Structural and molecular determinants of duplex functionality in a pure-rod retina

Award Number: SC2GM144198
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/21/2021
PERIOD OF PERFORMANCE END DATE: 06/30/2025

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Structural and molecular determinants of duplex functionality in a pure-rod retina - PROJECT SUMMARY/ABSTRACT: Proper function in the duplex retina depends on the utilization of rods and cones in the processing of visual information across the scotopic and photopic ranges of illumination. Importantly, when either type of photoreceptor is lost during retinal degeneration, the remaining photoreceptors, be they rods or cones, cannot perform the function of the opposite cell type. Most vertebrate retinae have this “duality” barrier and many current vision restoration efforts are targeted towards replacing the lost photoreceptor population. However, the elasmobranch L. erinacea (Little skate) has a pure-rod simplex retina, which can function under scotopic and photopic illumination. We have a poor understanding of what factors govern this remarkable plasticity in the skate retina, but a detailed knowledge of how this is achieved could hold the key to expanding the functional repertoire of surviving rods or cones in diseased duplex retinae. We propose that the skate retina exhibits a number of hybrid features on the molecular and ultrastructural levels that mediate its functional plasticity. Furthermore, our preliminary data leads us to two main hypotheses: 1) Skate rods function under scotopic and photopic conditions through a combination of morphological adaptations at the level of the synaptic terminal, and genetic adaptations at the level of opsin expression; and: 2) The skate retina exhibits multiple adaptions in the cell circuitry downstream of rods in order to accommodate for their functional plasticity. We have based these predictions on several pieces of preliminary data. First, a long-wavelength sensitive opsin (LWS) can be detected in the global genome of the skate. Second, multiple hybrid features are present at the ultrastructural level in the synaptic terminals of the skate rods. Third, there is a 3-fold increase in the number of postsynaptic processes that invaginate into a skate rod terminal, compared to rods from duplex retinae. Therefore, we will test our hypotheses in the following specific aims: Aim 1: To analyze differences in gene expression in light- and dark-adapted pure-rod retinae and uncover molecular mechanisms of functional plasticity. The objective of Aim 1 is to determine what molecular factors mediate this unusual functional plasticity. Aim 2: To determine the contribution of cell- and circuit-level structural and physiological characteristics mediating functional plasticity in a pure-rod retina. The objectives of Aim 2 are to determine if skate rods posses ultrastructural elements that mediate their functional plasticity, and if the retinal circuitry downstream of rods has evolved specific structural and physiological attributes in order to accommodate for a wider range of inputs. The proposed research is innovative because the simplex skate retina has evolved naturally to the present state and allows us the unique opportunity to study and describe the properties of rod circuitry within the context of an evolutionarily optimized visual system, unlike genetically modified rod-only models. It is significant because it will reveal fundamental principles of functional adaptation in a naturally occurring monotypic retina, which may lead to novel approaches in vision restoration efforts, especially after selective loss of photoreceptors.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $0 )
2026	2023	SAN FRANCISCO STATE UNIVERSITY	1600 HOLLOWAY AVE	SAN FRANCISCO	CA	94132	SAN FRANCISCO	USA	Biomedical Research and Research Training	000	3	3/3/2026	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $155,000 )
2023	2023	SAN FRANCISCO STATE UNIVERSITY	1600 HOLLOWAY AVE BUILDING NAD ROOM 358C	SAN FRANCISCO	CA	94132	SAN FRANCISCO	USA	Biomedical Research and Research Training	000	3	6/23/2023	NON-COMPETING CONTINUATION	$155,000
														Subtotal = $155,000

Issue Date FY: 2022 ( Subtotal = $155,000 )
2022	2022	SAN FRANCISCO STATE UNIVERSITY	1600 HOLLOWAY AVE BUILDING NAD ROOM 358C	SAN FRANCISCO	CA	94132	SAN FRANCISCO	USA	Biomedical Research and Research Training	001	2	6/13/2022	NON-COMPETING CONTINUATION	$155,000
2022	2021	SAN FRANCISCO STATE UNIVERSITY	1600 HOLLOWAY AVE BUILDING NAD ROOM 358C	SAN FRANCISCO	CA	94132	SAN FRANCISCO	USA	Biomedical Research and Research Training	000	1	11/17/2021	NEW	$0
														Subtotal = $155,000

Issue Date FY: 2021 ( Subtotal = $146,750 )
2021	2021	SAN FRANCISCO STATE UNIVERSITY	1600 HOLLOWAY AVE BUILDING NAD ROOM 358C	SAN FRANCISCO	CA	94132	SAN FRANCISCO	USA	Biomedical Research and Research Training	000	1	9/21/2021	NEW	$146,750
														Subtotal = $146,750

Grand Total All Awards = $456,750

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Structural and molecular determinants of duplex functionality in a pure-rod retina

Award Number: SC2GM144198

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 09/21/2021

PERIOD OF PERFORMANCE END DATE: 06/30/2025

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