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Engaging neuron-intrinsic signaling for axon growth after spinal cord injury

Award Number: R01NS099568
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: 07/15/2017
PERIOD OF PERFORMANCE END DATE: 06/30/2022

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Engaging neuron-intrinsic signaling for axon growth after spinal cord injury - For victims of spinal cord injury (SCI) to recover motor function, large numbers of damaged corticospinal tract (CST) axons would need to regenerate and re-connect with spinal inter- and motor neurons. However, axons do not regenerate in the mature injured spinal cord. Decades of research into this problem have yielded much insight into the mechanisms of axon growth and reasons why they fail in the SCI context, but no strategies enabling long-range axon regeneration have emerged, much less new treatments for SCI. To address this unmet need, my lab focuses on ways to re- activate in mature injured CNS neurons the intracellular axon growth signaling mechanisms that are active in developing neurons. The long-term goal of our research is to enable long-range axon regeneration and the re-establishment of functional circuitry in the injured spinal cord. We have recently observed that activation of RAF – MEK signaling in cortical motor neurons enables substantial regenerative growth of injured CST axons in genetically modified mice. We observed similar effects in wild type mice treated with repetitive transcranial stimulation (rTMS). The overall objective of this application is to thoroughly explore the extent of axon regenerative growth and synaptic re-connection that can be achieved by elevation of RAF – MEK signaling, or by rTMS. We plan to pursue the following three Specific Aims: First, to determine how much CST axon regeneration or sprouting can be stimulated in genetically modified B-RAF gain-of function mice subjected to three different established models of SCI. Second, we have generated a novel anterograde transsynaptic tracer by fusing the lectin WGA with the inducible Cre recombinase CreERT2. Upon activation by tamoxifen, this tracer triggers the expression of a protein of choice in postsynaptic neurons in a reporter mouse. We here plan to express the tracer in cortical motor neurons, to induce expression of a genetically encoded fluorescent Ca2+ indicator in their postsynaptic neurons. This will allow us to label new synapses formed by newly sprouting CST axons, and also to demonstrate their functional activity as reflected in Ca2+ transients. Finally, we plan to explore the power of rTMS to enable CST axon regeneration in wild type mice. Initial data indicate that the level of MEK activity correlates with rTMS-dependent CST axon regeneration. Therefore, we will use MEK1/2 conditional loss-of-function mice to test whether MEK activation is crucial for rTMS- dependent regeneration. The proposed study is innovative, as it takes advantage of new technical approaches (rTMS and the CreERT2WGA fusion tracer) to address the problem of long-range axon regeneration in the spinal cord. This research is also significant because it tests new concepts and strategies that may eventually contribute to axonal repair and functional recovery in SCI patients.


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: 2024 ( Subtotal = $0 )
2024	2021	THE WINIFRED MASTERSON BURKE MEDICAL RESEARCH INSTITUTE, INC	785 MAMARONECK AVE	WHITE PLAINS	NY	10605	WESTCHESTER	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	11/20/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = $611,854 )
2021	2021	WINIFRED MASTERSON BURKE MEDICAL RESEARCH INSTITUTE, INC, THE	785 MAMARONECK AVE	WHITE PLAINS	NY	10605	WESTCHESTER	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	7/16/2021	NON-COMPETING CONTINUATION	$611,854
														Subtotal = $611,854

Issue Date FY: 2020 ( Subtotal = $611,854 )
2020	2020	WINIFRED MASTERSON BURKE MEDICAL RESEARCH INSTITUTE, INC, THE	785 MAMARONECK AVE	WHITE PLAINS	NY	10605	WESTCHESTER	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	7/9/2020	NON-COMPETING CONTINUATION	$611,854
														Subtotal = $611,854

Issue Date FY: 2019 ( Subtotal = $611,854 )
2019	2019	WINIFRED MASTERSON BURKE MEDICAL RESEARCH INSTITUTE, INC, THE	785 MAMARONECK AVE	WHITE PLAINS	NY	10605	WESTCHESTER	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	6/19/2019	NON-COMPETING CONTINUATION	$611,854
														Subtotal = $611,854

Issue Date FY: 2018 ( Subtotal = $620,401 )
2018	2018	WINIFRED MASTERSON BURKE MEDICAL RESEARCH INSTITUTE, INC, THE	785 MAMARONECK AVE	WHITE PLAINS	NY	10605	WESTCHESTER	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	6/21/2018	NON-COMPETING CONTINUATION	$620,401
														Subtotal = $620,401

Issue Date FY: 2017 ( Subtotal = $669,912 )
2017	2017	WINIFRED MASTERSON BURKE MEDICAL RESEARCH INSTITUTE, INC, THE	785 MAMARONECK AVE	WHITE PLAINS	NY	10605	WESTCHESTER	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	7/10/2017	NEW	$669,912
														Subtotal = $669,912

Grand Total All Awards = $3,125,875

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Engaging neuron-intrinsic signaling for axon growth after spinal cord injury

Award Number: R01NS099568

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: 07/15/2017

PERIOD OF PERFORMANCE END DATE: 06/30/2022

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