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Physiological and Pathological Roles and Targets of DLK/JNK signaling in distal axons

Award Number: R21NS149559
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 06/15/2026
PERIOD OF PERFORMANCE END DATE: 05/31/2028

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Physiological and Pathological Roles and Targets of DLK/JNK signaling in distal axons - Abstract Axonal integrity is critical for nervous system function. After acute axonal injury, and in several neuropathological conditions, dual leucine-zipper kinase (DLK) signals via downstream c-Jun N- terminal kinases (JNKs) to convey signals from sites of axonal damage back to neuronal cell bodies. Proteins that are phosphorylated in response to such DLK/JNK pathway retrograde signaling, which include an array of transcription factors, are reasonably well understood. In contrast, although DLK and JNK also control the programmed self-destruction (Wallerian degeneration: WD) of damaged distal axons, axonal substrates of DLK/JNK that drive WD are far less clear. Moreover, recent studies suggest that basal DLK/JNK activity also maintains the integrity of healthy, undamaged distal axons. Again, though, the relevant DLK/JNK substrate(s) are unclear. This proposal builds on our comprehensive, unbiased phosphoproteomic identification of DLK substrates in healthy and damaged distal axons to provide unprecedented insights into these distinct roles of DLK/JNK signaling. In Aim 1 we will determine whether phosphorylation of the microtubule destabilizer Stathmin-1 is the master regulatory step that underlies DLK-dependent regulation of healthy axons. In Aim 2, we will build on our identification of an unexpected, widespread program of axonal dephosphorylation triggered by DLK in damaged axons. We will identify the functional consequences of this program for degradation of specific axonal proteins and for WD. This study will yield new insights into mechanisms that govern the balance between axonal integrity and degeneration and may identify new therapeutic targets to preserve axonal function in an array of neuropathological conditions


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 = $435,875 )
2026	2026	TEMPLE UNIVERSITY-OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	1805 N BROAD ST	PHILADELPHIA	PA	19122	PHILADELPHIA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	6/10/2026	NEW	$435,875
														Subtotal = $435,875

Grand Total All Awards = $435,875

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Physiological and Pathological Roles and Targets of DLK/JNK signaling in distal axons

Award Number: R21NS149559

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 06/15/2026

PERIOD OF PERFORMANCE END DATE: 05/31/2028

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