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Genetic method to selectively lesion axons or prune axonal terminals

Award Number: R21NS142521
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: 04/08/2026
PERIOD OF PERFORMANCE END DATE: 03/31/2028

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Genetic method to selectively lesion axons or prune axonal terminals - Abstract: It is well established that corticospinal tract (CST) axons have extensive axonal arborization throughout the brainstem and within spinal motor pools. How these CST terminals influence motor control through the brainstem in normal or lesioned animals remains unknown. Additionally, lesioning the CST within the pyramids or cervical spinal cord show deficits in skilled reaching. However, these CST lesions do not completely eliminate forelimb movements and locomotion remains intact, most likely mediated through rubrospinal, reticulospinal and propriospinal pathways. Whether or not these pathways require input from the CST to promote recovery has not been directly shown, only assumed through examination of CST sprouting into these nuclei. To better understand cortical control of brainstem motor nuclei, we have developed a novel genetic method to specifically lesion axons or their terminals while inducing minimal damage to the surround neurons or tracts. To induce a genetic lesion or pruning we have modified the human MAC-inhibitory protein CD59. This glycoprotein normally acts to protect cells from completement mediated lysis, however, intermedilysin (ILY) released by Streptococcus intermedius binds to the human but not rat form of CD59 to create a cytolytic pore. hCD59 expression in rodent models is a very effective mechanism to selectively ablate a variety of cells in vivo, even neurons, however, we found that it was poorly transported into axons. To increase penetrance into axons, we exchanged the endogenous GPI linkage with several know to be transported into axons. We engineered a novel hCD59 - thy1.1 GPI-linkage chimera showing excellent transport into axons and terminals and efficiently induced axonal severing in the presence of ILY. Here we hypothesize that this tool will be an effective method to dissect the motor control responsibilities of CST collaterals in extrapyramidal motor systems. There are 2 aims to the study. Aim 1 will examine the contribution of the regional distribution of CST after genetic lesioning of the CST axons in the cerebral peduncles, rostral pyramids, and cervical spinal cord. Aim 2 will examine the contribution of CST axonal terminals within specific brainstem nuclei known to be involved in mediating recovery after SCI. Outcome measure will include histological assessment of axon severing, immune response, gliosis and myelination at ILY injection site, as well as, behavioral assessment of skill forelimb use in normal and SCI rehabilitated rats. This technique could become a useful tool to examine the functional contribution of axonal collaterals and terminals within various motor or sensory nuclei.


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 = $237,750 )
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	4/7/2026	NEW	$237,750
														Subtotal = $237,750

Grand Total All Awards = $237,750

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Genetic method to selectively lesion axons or prune axonal terminals

Award Number: R21NS142521

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: 04/08/2026

PERIOD OF PERFORMANCE END DATE: 03/31/2028

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