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Molecular Determinants for In vivo Functional Reprogramming of Cortical Output Neurons and Circuits

Award Number: R01NS128106
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: 07/10/2022
PERIOD OF PERFORMANCE END DATE: 06/30/2027

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Molecular Determinants for In vivo Functional Reprogramming of Cortical Output Neurons and Circuits - PROJECT SUMMARY/ABSTRACT Currently there is no successful treatment that restores damaged brain circuitry. Neuron loss by either neurodegenerative diseases or trauma causes neurological and cognitive dysfunction, posing a great burden for human health. There is a critical need to find strategies for neural circuit repair. Direct reprogramming approaches hold great promise for brain repair. Their success in functional circuit restoration will depend on their capacity to convert other cells into neurons with functions matching those of the neurons damaged in a circuit. This precise conversion has been observed in the mouse cerebral cortex between cortical output (corticofugal) neurons, which can acquire the connectivity properties, including long-range projections, typical of other corticofugal subtypes. Though this is a promising step forward toward circuit repair, this precise conversion has been observed when reprogramming is induced at embryonic or immature states. The mechanisms that preclude reprogramming in differentiated neurons or the mechanisms that keep neuron identity unchanged throughout life are not understood. Hence, our goal is to investigate mechanisms critical for maintaining neuron subtype identity in differentiated neurons and determine how they limit reprogramming over time. This will reveal barriers that preclude functional conversion between neuron subtypes in vivo. We propose to investigate these mechanisms in corticofugal neurons, specifically in the context of in vivo reprogramming of Corticothalamic neurons (CTn) to produce Subcerebral projection neurons (SCn), a clinically relevant neuron subtype that degenerates in Amyotrophic lateral sclerosis and whose axons are damaged by spinal cord injury. In this proposal we will investigate whether identity maintenance mechanisms can be manipulated for in vivo reprogramming of CTn into functional SCn (Aim 1), we will determine whether these mechanisms can be inactivated in mature CTn to eliminate barriers that preclude CTn conversion into SCn (Aim 2), and we will elucidate the underlying downstream signals that preclude conversion of CTn into SCn in vivo (Aim 3).


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 = $374,550 )
2025	2025	THE ADMINISTRATORS OF TULANE EDUCATIONAL FUND	6823 SAINT CHARLES AVE	NEW ORLEANS	LA	70118	ORLEANS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	7/17/2025	NON-COMPETING CONTINUATION	$374,550
														Subtotal = $374,550

Issue Date FY: 2024 ( Subtotal = $363,314 )
2024	2024	ADMINISTRATORS OF THE TULANE EDUCATIONAL FUND, THE	6823 SAINT CHARLES AVE	NEW ORLEANS	LA	70118	ORLEANS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	7/24/2024	NON-COMPETING CONTINUATION	$363,314
														Subtotal = $363,314

Issue Date FY: 2023 ( Subtotal = $374,550 )
2023	2023	ADMINISTRATORS OF THE TULANE EDUCATIONAL FUND, THE	6823 SAINT CHARLES AVE	NEW ORLEANS	LA	70118	ORLEANS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	7/7/2023	NON-COMPETING CONTINUATION	$374,550
														Subtotal = $374,550

Issue Date FY: 2022 ( Subtotal = $372,200 )
2022	2022	ADMINISTRATORS OF THE TULANE EDUCATIONAL FUND, THE	6823 SAINT CHARLES AVE	NEW ORLEANS	LA	70118	ORLEANS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	7/7/2022	NEW	$372,200
														Subtotal = $372,200

Grand Total All Awards = $1,484,614

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Molecular Determinants for In vivo Functional Reprogramming of Cortical Output Neurons and Circuits

Award Number: R01NS128106

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: 07/10/2022

PERIOD OF PERFORMANCE END DATE: 06/30/2027

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