Wednesday, February 18, 2026 2/18/2026

Unexpected Function of Inflammasomes in Axon Pruning: Focus on NLRP1

Award Number: R01NS117133
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: 02/01/2021
PERIOD OF PERFORMANCE END DATE: 01/31/2027

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Unexpected Function of Inflammasomes in Axon Pruning: Focus on NLRP1 - Project Summary/Abstract Neurons are capable of activating pathways that induce either the degeneration of the entire cell by apoptosis or to selectively degenerate only the axons. Physiological axon-specific degeneration, known as axon pruning, is important as it allows neurons to remove excessive or misguided axons and permit plasticity in neuronal connections. Aberrant pruning is observed in several neurodegenerative diseases, including Alzheimer’s Disease (AD). However, exactly how neurons activate this pathway to degenerate axons in physiological or pathological situations of AD is unclear. We have investigated the apoptosis and axon pruning pathways in a microfluidic chamber-based model utilizing sympathetic neurons. Upon nerve growth factor (NGF) deprivation, these neurons can induce either apoptosis (when NGF is deprived from both soma and axon compartments) or axon pruning (when NGF is deprived from only the axon compartment). Our research has identified substantial overlap but also distinct differences between the apoptosis and axon pruning pathways. For example, while caspase-9 (Casp9) and caspase-3 (Casp3) are required for both pathways, their activation is dependent on the apoptosome during apoptosis but is surprisingly independent of the apoptosome during axon pruning. While investigating the mechanism by which caspases are activated during pruning, we unexpectedly found that the inflammasome pathway plays an important function in axon pruning. Inflammasomes have been studied primarily in immune cells in the context of pathogen signaling. These are multi-protein complexes formed in response to pathogenic or danger stimuli, which result in activation of the proinflammatory caspase, caspase-1 (Casp1). Strikingly, we found that Casp1 and NLRP1 (a key component of a particular inflammasome) are both essential for axon pruning. These results are surprising as axon pruning does not involve pathogen exposure. In this proposal, we will identify the specific inflammasome pathway components that are critical for axon pruning and conduct mechanistic experiments to define this novel function of NLRP1 in neurons. In Aim 1, we will define the specific inflammasome proteins that are essential for axon pruning, and determine where they act in the known pruning pathway. In Aim 2, we will define the role of IL-1β/IL-18 in axon pruning. Our focus in Aim 3 will be to conduct mechanistic experiments to examine how NLRP1 is activated in the context of axon pruning. Importantly, in Aim 4 we will focus on AD and investigate whether the pathological degeneration of synapses and axons in AD are mediated by NLRP1. We will examine this in a microfluidic model of Aβ-induced axon degeneration in vitro as well as in a mouse model of AD in vivo where we will examine if NLRP1 deficiency reduces AD pathology and behavioral defects. This project opens an exciting new avenue of research into this unexpected function of the NLRP1 inflammasome in neurons.


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	2025	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	1/28/2026	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2025 ( Subtotal = $547,528 )
2025	2025	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	3/5/2025	NON-COMPETING CONTINUATION	$492,776
2025	2025	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	3	8/5/2025	NON-COMPETING CONTINUATION	$54,752
														Subtotal = $547,528

Issue Date FY: 2024 ( Subtotal = $650,493 )
2024	2024	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	2/28/2024	EXTENSION WITH OR WITHOUT FUNDS	$502,572
2024	2024	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	2	8/12/2024	EXTENSION WITH OR WITHOUT FUNDS	$92,080
2024	2024	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	2	5/14/2024	EXTENSION WITH OR WITHOUT FUNDS	$55,841
														Subtotal = $650,493

Grand Total All Awards = $1,198,021

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Unexpected Function of Inflammasomes in Axon Pruning: Focus on NLRP1

Award Number: R01NS117133

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: 02/01/2021

PERIOD OF PERFORMANCE END DATE: 01/31/2027

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