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Traumatic Axonopathy in the CNS as Wallerian degeneration

Award Number: R01NS114397
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: 01/01/2021
PERIOD OF PERFORMANCE END DATE: 11/30/2025

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Traumatic Axonopathy in the CNS as Wallerian degeneration - PROJECT SUMMARY In this application we propose that traumatic axonal injury (TAI) leads to an active axonopathy with the molecular features of Wallerian degeneration and that targeting some of the relevant signals may protect axons as well as brain systems. This hypothesis is based on recent findings in our laboratory showing that axonal breakdown after diffuse TAI depends on the activation of Sterile Alpha and TIR Motif Containing 1 (SARM1) signaling and that molecular interventions to block SARM1 lead to significant gains in preserving axons and rescuing functions/behaviors that rely on axonal integrity. The case of TAI is unique in the sense that that many axons are only partially injured and are potentially salvageable, therefore blocking Wallerian-type self-destruction may afford long-term neuroprotection and change the prognosis of traumatic brain injury. Our proposal is organized in three specific aims. In Aim 1 we establish that TAI in an index CNS tract, i.e. the corticospinal system, leads to progressive axonopathy with the molecular signatures of Wallerian degeneration, i.e. activation of SARM1. In Aim 2 we ask whether axonal protection by genetic or pharmacological blockade of SARM1 signaling in the injured corticospinal tract translate into protection at the systems level, i.e. prevention of retrograde atrophy of corticospinal neurons, preservation of corticospinal connectivity and rescue of CST-dependent motor skills. In Aim 3 we explore the synergistic role of the mitogen-activated protein kinase (MAPK) pathway, specifically signaling by the dual leucine zipper kinase (DLK) and related leucine zipper kinase (LZK), in corticospinal axonal degeneration following TAI. The MAPK pathway signals general neuronal responses to injury and there is evidence that specific members of the pathway cooperate with SARM1-related signals in triggering or affecting the outcome of Wallerian degeneration. To achieve the previous aims, we use a complement of molecular genetic tools including knockout mice, dominant negative strategies and genome editing with CRISPR-Cas9, metabolomic assessments, CLARITY-based high-resolution neuropathology, structural and functional connectivity markers, behavioral testing, and small molecules as probes for molecular targets and also as therapeutic agents (the NAMPT inhibitor FK866 that serves as indirect inhibitor of SARM1 and the pan-Aurora inhibitor tozasertib that blocks DLK/LZK signaling). In summary, here we explore specific molecular mechanisms related to Wallerian degeneration and, in the course of doing this, we establish molecular targets for potential pharmacological interventions in traumatic brain injury.


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: 2025 ( Subtotal = $428,376 )
2025	2025	THE JOHNS HOPKINS UNIVERSITY	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	11/29/2024	NON-COMPETING CONTINUATION	$428,376
														Subtotal = $428,376

Issue Date FY: 2024 ( Subtotal = $461,693 )
2024	2024	THE JOHNS HOPKINS UNIVERSITY	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	4	4/17/2024	NON-COMPETING CONTINUATION	$33,317
2024	2024	THE JOHNS HOPKINS UNIVERSITY	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	2/5/2024	NON-COMPETING CONTINUATION	$428,376
														Subtotal = $461,693

Issue Date FY: 2023 ( Subtotal = $475,972 )
2023	2023	JOHNS HOPKINS UNIVERSITY, THE	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	12/19/2022	NON-COMPETING CONTINUATION	$428,376
2023	2023	JOHNS HOPKINS UNIVERSITY, THE	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	3	2/2/2023	NON-COMPETING CONTINUATION	$47,596
														Subtotal = $475,972

Issue Date FY: 2022 ( Subtotal = $475,972 )
2022	2022	JOHNS HOPKINS UNIVERSITY, THE	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	11/23/2021	NON-COMPETING CONTINUATION	$428,375
2022	2022	JOHNS HOPKINS UNIVERSITY, THE	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	2	3/24/2022	NON-COMPETING CONTINUATION	$47,597
														Subtotal = $475,972

Issue Date FY: 2021 ( Subtotal = $475,972 )
2021	2021	JOHNS HOPKINS UNIVERSITY, THE	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	12/21/2020	NEW	$475,972
														Subtotal = $475,972

Grand Total All Awards = $2,317,985

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Traumatic Axonopathy in the CNS as Wallerian degeneration

Award Number: R01NS114397

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: 01/01/2021

PERIOD OF PERFORMANCE END DATE: 11/30/2025

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