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The role of novel lincRNAs in regulating RGC survival after injury

Award Number: R01EY034531
ORGANIZATION: NATIONAL EYE INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 03/01/2024
PERIOD OF PERFORMANCE END DATE: 02/28/2029

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The role of novel lincRNAs in regulating RGC survival after injury - Abstract Retinal ganglion cells (RGCs) are the only projection neurons in the retina that relay visual information to the brain. These neurons, which collectively form the optic nerve, are highly vulnerable when their axons are damaged. Preclinical animal studies have tested several approaches to promote RGC survival following axonal damage. Clinical trials aimed at assessing the neuroprotective effects are currently underway. However, attaining strong neuroprotection for patients suffering from optic neuropathy remains an elusive goal. Long noncoding RNAs (LncRNAs) are a diverse class of transcribed RNAs, defined as transcripts with lengths exceeding 200 nucleotides that do not encode proteins. Although several lncRNAs have been shown to play vital roles in regulating gene expression networks in the central nervous system (CNS), the functional roles of the majority of lncRNAs are unknown. In our recent effort to investigate RGC type-specific gene expression, we performed RNAsequencing (RNA-seq) on distinct RGC populations. Through this work, we identified hundreds of lncRNAs that are uniquely induced in different RGC types after axonal injury. The functions of these lncRNAs remain to be determined. To investigate lncRNAs’ functional roles, and to examine whether modulating the expression of injury-induced lncRNAs affects RGC survival after axonal injury, we generated adeno-associated viruses (AAV) expressing shRNAs against select lncRNAs, and carried out an in vivo screen using optic nerve crush (ONC). Through this work, we find that silencing one lncRNA results in striking neuroprotection for RGCs after ONC. This lncRNA is a long intergenic non-coding RNA (lincRNA) which we name optic nerve injury-induced lncRNA 1 or Onil1. Like the vast majority of lncRNAs that we found to be differentially expressed in RGCs, virtually nothing is known about this lincRNA. Overall, our study provides us with an exciting and unique opportunity to investigate the role of lncRNAs in regulating RGC survival after injury, and elucidate the possible molecular mechanisms underlying this process. In this proposal, we seek to combine in vivo models of optic nerve injury, functional and behavioral assays, and bioinformatics to investigate the contribution of Onil1 and other lncRNAs in regulating RGC survival. To this end, in Aim 1, we will systemically assess the extent of RGC protection conferred by silencing lncRNAs in adult RGCs after ONC. In Aim 2, we will assess whether silencing lncRNA induces RGC protection and functional rescue in mouse models of glaucoma. Lastly, in Aim 3, we will use immunostaining, RNA-seq, ATAC- seq and ChIRP-MS to investigate the mechanisms by which Onil1 regulates RGC survival.


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 = $410,000 )
2026	2026	THE UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Vision Research	000	3	2/12/2026	NON-COMPETING CONTINUATION	$410,000
														Subtotal = $410,000

Issue Date FY: 2025 ( Subtotal = $410,000 )
2025	2025	THE UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Vision Research	000	2	2/18/2025	NON-COMPETING CONTINUATION	$410,000
														Subtotal = $410,000

Issue Date FY: 2024 ( Subtotal = $410,000 )
2024	2024	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER, THE	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Vision Research	000	1	2/21/2024	NEW	$410,000
														Subtotal = $410,000

Grand Total All Awards = $1,230,000

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The role of novel lincRNAs in regulating RGC survival after injury

Award Number: R01EY034531

ORGANIZATION: NATIONAL EYE INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 03/01/2024

PERIOD OF PERFORMANCE END DATE: 02/28/2029

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