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Mechanisms of axoglial interactions at the paranodal junction

Award Number: K99EY037780
ORGANIZATION: NATIONAL EYE INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 04/15/2026
PERIOD OF PERFORMANCE END DATE: 03/31/2028

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Mechanisms of axoglial interactions at the paranodal junction - PROJECT SUMMARY. Proper CNS function requires intricate axon-glia interactions. In the optic nerve, for example, each myelinating oligodendrocyte (OL) physically contacts up to 60 axons, forming the largest intercellular junction in vertebrates - the paranodal junction (PNJ). The PNJ anchors the myelin sheath to the axon, is the main mechanism responsible for ion channel clustering at the nodes of Ranvier and serves as a central point of communication between the axon and OLs. Recently, more and more evidence on disrupted nodes and paranodes have been reported in neurological and psychiatric disorders, axonal injury and regeneration, and aging. However, our knowledge of this unique axon-glia interaction is still very limited, especially about its molecular composition. This reflects the significant technical challenges associated with the lipid-rich and insoluble nature of the PNJ, as well as the lack tools to reliably visualize, disrupt, and evaluate the axon-glia interactions in vivo. Lastly, validating new paranodal proteins requires reliable antibodies, the lack of which has hindered progression of scientific discoveries and caused major concerns in reproducibility. To overcome these challenges, I have designed a reliable and medium-throughput pipeline for novel protein discovery at axoglial junctions with rapid validation and downstream functional analyses in vivo. I propose to combine proximity-biotinylation based subdomain proteomic profiling, CRISPR/Cas9-based genome editing, and a highly efficient and cell type-specific AAV-delivery system. My early postdoctoral work has established the importance of the paranodal scaffolding protein AnkyrinG (AnkG), which will be used as a molecular entry point to further dissect the PNJ. In Aim1, I propose to use proximity proteomic approach to bypass the difficulty in efficient protein isolation and identification at the PNJ. Our lab has developed a unique conditional knock-in mouse model with TurboID fused to the C-terminus of the endogenous AnkG protein, where proteins enriched at the PNJ can be covalently labeled with biotin, efficiently purified and identified by mass spectrometry. I will functionally validate the candidate proteins using an optimized CRISPR-Cas9 based AAV-mediated genome- editing system to efficiently target oligodendrocytes in vivo. This allows for direct visualization of the endogenous protein in addition to gain- and loss-of-function experiments in vivo. In Aim2, I will begin with the functional analysis of a novel candidate at the PNJ, Palm2. In Aim3, I will examine the contribution of the novel candidates identified at PNJ to axonal injury repair using an optic nerve crush model. Successful completion of this project will reveal the functions of novel oligodendroglial PNJ proteins, thereby bridging a critical knowledge gap in axon-glia interactions and myelination. Moreover, our optimized pipeline for in vivo screening has the potential to transform future studies with genetic manipulation of OLs. It eliminates concerns associated with unvalidated antibodies and provides a rapid and reliable method for screening oligodendroglial protein localization and function.


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 = $120,902 )
2026	2026	BAYLOR COLLEGE OF MEDICINE	1 BAYLOR PLZ	HOUSTON	TX	77030	HARRIS	USA	Vision Research	000	1	4/13/2026	NEW	$120,902
														Subtotal = $120,902

Grand Total All Awards = $120,902

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Mechanisms of axoglial interactions at the paranodal junction

Award Number: K99EY037780

ORGANIZATION: NATIONAL EYE INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 04/15/2026

PERIOD OF PERFORMANCE END DATE: 03/31/2028

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