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Combinatorial Manipulation of Transcription Factors to Promote CNS Regeneration

Award Number: R01NS083983
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: 07/15/2013
PERIOD OF PERFORMANCE END DATE: 02/28/2026

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Combinatorial Manipulation of Transcription Factors to Promote CNS Regeneration - PROJECT SUMMARY In adults, axons in the central nervous system (CNS) generally fail to regenerate after they are lost to injury or disease, leading to permanent and incurable disability. Axon growth is prevented by a hostile growth environment, as well as a developmental loss in the intrinsic capacity for axon growth as CNS neurons age. Transcription factors (TFs) interact with DNA and coordinate the production of broad sets of cellular materials, and have emerged as important therapeutic targets to boost regenerative ability within injured neurons. For example, forced re-expression of a pro-regenerative TF called KLF6 in adult neurons can improve their capacity for axon growth after spinal injury. We will now test three complementary and mutually supportive strategies to enhance the promising pro-regenerative properties of KLF6. First, using a novel bioinformatics pipeline, we have predicted additional TFs that functionally interact with KLF6 and verified their ability to synergistically enhance axon growth when combined with KLF6 in cell culture models of axon growth. We will therefore perform in vivo tests of three selected factors, EOMES, NR5A2, and RARB, for the ability to enhance KLF6’s pro-regenerative properties in animal models of spinal cord injury. Second, we will supplement these TF interventions with transplants of growth- permissive stem cells into sites of spinal injury. These grafts will alleviate persistent growth inhibition in the spinal cord environment, and thus unmask the pro-regenerative effects of TF treatments. Finally, we will harness a newly developed gene therapy vector that enables retrograde delivery of genes with unprecedented efficiency. Injection of this vector to the spinal cord results in widespread gene expression in injured neurons throughout the brainstem, midbrain, and motor cortex. This delivery system engages a larger number and a wider diversity of cell types than the current practice of direct brain injection, thus maximizing the chance of achieving functional gains after spinal injury. Throughout these aims, tissue clearing and 3D microscopy will reveal new anatomical details of the evoked regeneration. Bringing together these cutting-edge improvements to a TF-centered strategy will move the field toward novel and effective treatments for individuals suffering from the debilitating consequences of CNS injury.


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 = $0 )
2025	2023	MARQUETTE UNIVERSITY	313 N 13TH ST	MILWAUKEE	WI	53233	MILWAUKEE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	10	5/1/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $379,626 )
2023	2023	MARQUETTE UNIVERSITY	915 W WISCONSIN AVE RM 175	MILWAUKEE	WI	53233	MILWAUKEE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	10	3/16/2023	NON-COMPETING CONTINUATION	$379,626
														Subtotal = $379,626

Issue Date FY: 2022 ( Subtotal = $379,626 )
2022	2022	MARQUETTE UNIVERSITY	915 W WISCONSIN AVE RM 175	MILWAUKEE	WI	53233	MILWAUKEE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	9	4/1/2022	NON-COMPETING CONTINUATION	$37,964
2022	2022	MARQUETTE UNIVERSITY	915 W WISCONSIN AVE RM 175	MILWAUKEE	WI	53233	MILWAUKEE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	9	3/1/2022	NON-COMPETING CONTINUATION	$341,662
														Subtotal = $379,626

Issue Date FY: 2021 ( Subtotal = $379,626 )
2021	2021	MARQUETTE UNIVERSITY	915 W WISCONSIN AVE RM 175	MILWAUKEE	WI	53233	MILWAUKEE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	8	3/7/2021	NON-COMPETING CONTINUATION	$379,626
														Subtotal = $379,626

Issue Date FY: 2020 ( Subtotal = $379,626 )
2020	2020	MARQUETTE UNIVERSITY	915 W WISCONSIN AVE RM 175	MILWAUKEE	WI	53233	MILWAUKEE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	7	3/12/2020	NON-COMPETING CONTINUATION	$379,626
2020	2019	MARQUETTE UNIVERSITY	915 W WISCONSIN AVE RM 175	MILWAUKEE	WI	53233	MILWAUKEE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	6	1/14/2020	COMPETING CONTINUATION	-$2,240
2020	2017	MARQUETTE UNIVERSITY	915 W WISCONSIN AVE RM 175	MILWAUKEE	WI	53233	MILWAUKEE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	1/14/2020	NON-COMPETING CONTINUATION	$2,240
														Subtotal = $379,626

Issue Date FY: 2019 ( Subtotal = $387,370 )
2019	2019	MARQUETTE UNIVERSITY	915 W WISCONSIN AVE RM 175	MILWAUKEE	WI	53233	MILWAUKEE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	003	6	8/7/2019	COMPETING CONTINUATION	$4,012
2019	2019	MARQUETTE UNIVERSITY	915 W WISCONSIN AVE RM 175	MILWAUKEE	WI	53233	MILWAUKEE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	6	3/8/2019	COMPETING CONTINUATION	$387,370
2019	2017	MARQUETTE UNIVERSITY	915 W WISCONSIN AVE RM 175	MILWAUKEE	WI	53233	MILWAUKEE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	5	8/7/2019	NON-COMPETING CONTINUATION	-$4,012
2019	2017	MARQUETTE UNIVERSITY	915 W WISCONSIN AVE RM 175	MILWAUKEE	WI	53233	MILWAUKEE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	3/6/2019	NON-COMPETING CONTINUATION	$0
														Subtotal = $387,370

Issue Date FY: 2017 ( Subtotal = $329,219 )
2017	2017	MARQUETTE UNIVERSITY	915 W WISCONSIN AVE RM 175	MILWAUKEE	WI	53233	MILWAUKEE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	5	6/6/2017	NON-COMPETING CONTINUATION	$329,219
2017	2016	MARQUETTE UNIVERSITY	915 W WISCONSIN AVE RM 175	MILWAUKEE	WI	53233	MILWAUKEE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	4	10/27/2016	EXTENSION WITH OR WITHOUT FUNDS	$95,317
2017	2015	MARQUETTE UNIVERSITY	915 W WISCONSIN AVE RM 175	MILWAUKEE	WI	53233	MILWAUKEE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	10/27/2016	NON-COMPETING CONTINUATION	-$95,317
														Subtotal = $329,219

Issue Date FY: 2016 ( Subtotal = $329,219 )
2016	2016	MARQUETTE UNIVERSITY	P.O. BOX 1881	MILWAUKEE	WI	53201	MILWAUKEE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	8/22/2016	EXTENSION WITH OR WITHOUT FUNDS	$329,219
														Subtotal = $329,219

Issue Date FY: 2015 ( Subtotal = $329,219 )
2015	2015	MARQUETTE UNIVERSITY	P.O. BOX 1881	MILWAUKEE	WI	53201	MILWAUKEE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	5/13/2015	NON-COMPETING CONTINUATION	$329,219
														Subtotal = $329,219

Issue Date FY: 2014 ( Subtotal = $325,927 )
2014	2014	MARQUETTE UNIVERSITY	P.O. BOX 1881	MILWAUKEE	WI	53201	MILWAUKEE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	5/8/2014	NON-COMPETING CONTINUATION	$325,927
														Subtotal = $325,927

Issue Date FY: 2013 ( Subtotal = $329,219 )
2013	2013	MARQUETTE UNIVERSITY	P.O. BOX 1881	MILWAUKEE	WI	53201	MILWAUKEE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	7/12/2013	NEW	$329,219
														Subtotal = $329,219

Grand Total All Awards = $3,548,677

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Combinatorial Manipulation of Transcription Factors to Promote CNS Regeneration

Award Number: R01NS083983

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: 07/15/2013

PERIOD OF PERFORMANCE END DATE: 02/28/2026

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