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Project

Zinc chelation to promote axon regeneration after spinal cord injury

Funder: Craig H Neilsen Foundation

Funding period
USD 149 K
Funding amount
Abstract
The objective of this proposal is to develop a novel approach to SCI treatment using zinc chelation. The failure of damaged axons to regrow is a major contributing factor to sustained functional deficits following SCI. Regrowth of axons, whether it is long distance regeneration that re-establishes original connections or shorter sprouting that re-wires local plastic circuits, is likely to underlie spontaneous and treatment-induced functional recovery. Recent data from Dr. Benowitz’s laboratory (mentor) showed that the ion zinc (Zn2+) is increased in injured neurons after mouse optic nerve crush, and that blocking the post-crush Zn2+ accumulation using Zn2+ chelation methods strongly promotes axon regeneration. Given the similarities between optic nerve and spinal cord, I propose to test the hypothesis that Zn2+ chelation will promote axon regrowth after SCI. I will test this hypothesis through three focused specific aims. First, I will quantify the Zn2+ in the motor and sensory neurons and examine the time-course of changes in Zn2+ following SCI. Further, I will optimize post-SCI Zn2+ chelation in motor and sensory neurons, examining both local delivery and systemic application using clinically approved chelating agents. Finally, I will determine whether Zn2+ chelation promotes motor and sensory axon regrowth after SCI in mice. Specifically, I plan to conduct mid-thoracic hemisection injuries, tract tracing, and Zn2+ chelation treatment in genetically normal mice. I will assess Zn2+ accumulation in brain, spinal cord, and dorsal root ganglia by autometallography. I plan to assess axon sprouting and regeneration of the traced corticospinal tract (motor) and the traced gracile fasciculus (sensory), using measures of the furthest regenerating axons, collateral axon sprouting, and axon density. Rubrospinal tract regeneration and new corticospinal-interneuron connections will also be examined. I have found that baseline (uninjured adult) levels of Zn2+ in the cell bodies of brain neurons that project to the spinal cord are already elevated in comparison to the projection neurons of the retina, suggesting that axons associated with these neurons may experience constitutive axon growth suppression by Zn2+, and that Zn2+ chelation may release this suppression and induce spinal cord axon regeneration regardless of whether the predicted SCI-induced increase in Zn2+ accumulation occurs in these neurons. I will perform this project under the mentorship of Dr. Benowitz, who discovered the benefit of Zn2+ chelation for optic nerve axon regeneration, and has expertise in the required assessments of Zn2+ chelation and quantification. Dr. Benowitz has experience with SCI research, as do I. If data from the proposed project support my hypotheses, I will be particularly encouraged because systemic Zn2+ chelation has been safely used for other clinical indications, increasing the translational potential of this approach for clinical SCI. (CHN: SCIRTS chn:wdg)

 
201
Projects
USD 52.5 M
Aggregated funding amount
USD 261 K
Average funding amount
Project list item
Stimulation to Enhance Migration and Synaptic Integration of Neural Grafts

Craig H Neilsen Foundation to Matthew Hogan, Philip J Horner

USD 150,000
2019 - 2021
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The intraspinal serotonergic system regulates micturition reflexe after SCI

Craig H Neilsen Foundation to Yu-Shang Lee

USD 300,000
2019 - 2021
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Plasticity Of Reticulospinal Pathways Following Spinal Cord Injury

Craig H Neilsen Foundation to Frederic Bretzner

USD 300,000
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Human ApoE and its impact on plasticity and recovery after SCI

Craig H Neilsen Foundation to Warren Alilain, Lance Johnson

USD 300,000
2019 - 2021
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Molecular control over motor circuit remodeling

Craig H Neilsen Foundation to Edmund Roy Hollis, Nadjat Serradj

USD 300,000
2019 - 2021
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Investigating microtubule regulation in axon and branch regeneration

Craig H Neilsen Foundation to Le Ma, Angelo C Lepore

USD 300,000
2019 - 2021
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Biological light stimulation to restore function after SCI

Craig H Neilsen Foundation to Ute Hochgeschwender, Ute Hochgeschwender, Eric D. Petersen, Griffin E. Kendziorski

USD 300,000
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Functional map of spinal cord stimulation

Craig H Neilsen Foundation to CJ Heckman

USD 600,000
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Metabolic reprograming of glial cells promotes axon regeneration in the CNS

Craig H Neilsen Foundation to Yuanquan Song

USD 300,000
2019 - 2021
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Novel and potent compounds that promote axon growth

Craig H Neilsen Foundation to Vance P. Lemmon, Marc Giulianotti, Hassan Al-Ali, Sixue Chen, John Bixby

USD 600,000
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Project list item
Novel chemical approaches for specific targeting of CSPGs to restore function after SCI

Craig H Neilsen Foundation to Linda Carol Hsieh-Wilson, Elizabeth Jane Bradbury

USD 600,000
2019 - 2022
Project list item
Neural Pathways and Recovery of Motor Function with Epidural Stimulation

Craig H Neilsen Foundation to Jessica Maria D'Amico, Claudia Angeli, Susan Harkema

USD 300,000
2019 - 2021
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Determining spinal alterations in sexual reflex control.

Craig H Neilsen Foundation to Lique Martina Coolen, James Walker Wiggins, James Walker Wiggins, Sid Gaikwad

USD 599,976
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Project list item
Leveraging activity and guidance cues to promote targeting of CST outgrowth

Craig H Neilsen Foundation to Jack Martin

USD 600,000
2018 - 2021
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Preventing changes in mental health in a rat model of spinal cord injury

Craig H Neilsen Foundation to Karim Fouad

USD 300,000
2018 - 2020
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Toll-like receptor 4 signaling in chronic neuropathic pain after SCI

Craig H Neilsen Foundation to Armin Blesch, Zhiyong Tan, Fletcher White

USD 300,000
2018 - 2020
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A Placental Stem Cell Derived Treatment for Acquired Spinal Cord Injury

Craig H Neilsen Foundation to Diana Farmer, Aijun Wang

USD 300,000
2018 - 2020
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Transplantation of pre-vascularized scaffolds for spinal cord injury repair

Craig H Neilsen Foundation to Peter Galie, Itzhak Fischer, Ying Jin

USD 297,978
2018 - 2020
Project list item
MECHANISMS OF OPIOID RESISTANCE AFTER SPINAL CORD INJURY

Craig H Neilsen Foundation to Carmen W Dessauer, Michelle Hook, Edgar Walters

USD 600,000
2018 - 2021
Project list item
Axonal mRNA transport and local translation as a potentially crucial mechanism for spinal cord axon

Craig H Neilsen Foundation to Jian Zhong

USD 300,000
2018 - 2020
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