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Myelin Junction Therapy in Peripheral Neuropathies

Award Number: R01NS115748
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: 03/15/2020
PERIOD OF PERFORMANCE END DATE: 12/31/2024

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Myelin Junction Therapy in Peripheral Neuropathies - Schwann cell extends its cell membrane to wrap around segments of axon concentrically for multiple layers and forms the myelin. Demyelination removes segments of myelin along the nerve fibers. This pathology occurs in a group of neurological disorders with collectively high prevalence: Guillain-Barre syndrome, chronic inflammatory demyelinating polyneuropathy, multifocal motor neuropathy, hereditary neuropathy with liability to pressure palsies (HNPP) and multiple sclerosis. Myelin may be abnormally developed (dysmyelination) in inherited neurological diseases. Therefore, it is highly desirable if molecular targets can be identified and manipulated to repair myelin. Motivated by our recent observations, we propose this study to deals with myelin junction proteins and p21 activated kinase (PAK)-related pathway that likely become the molecular target. Our studies have discovered that hyperactive p21-activated kinase-1 (PAK1) plays a key role in removal of myelin junctions in matured myelin. These junctions are made by proteins that seal the small spaces between layers of myelin. Removal of myelin junctions lead to excessively permeable myelin in a mouse with a deletion of one of two copies of Pmp22 genes (Pmp22+/-), an authentic model for HNPP. The junction removal is an early event upstream to the segmental demyelination. In contrast, we recently observed that deficiency of PAK2 (another family member of PAK in the peripheral nerves) in Schwann cells results in severe dysmyelination with pathological changes similar to that seen in patients with congenital hypomyelination, suggesting a critical function of PAK2 in myelin development. Thus, relative levels of PAK1/PAK2 activation may differentially affect myelin development and maintenance. In this study, we will first verify the causal relationship between hyperactive PAK1 and removal of myelin junctions / demyelination in several peripheral neuropathy mouse models. We will then examine how PAK2 regulates myelin development. Finally, we will test whether PAK can be targeted to treat other peripheral nerve diseases. 1


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	METHODIST HOSPITAL, THE	6670 BERTNER AVE	HOUSTON	TX	77030	HARRIS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	4	11/15/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$231,174
2025	2022	WAYNE STATE UNIVERSITY	5700 CASS AVE STE 4900	DETROIT	MI	48202	WAYNE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	11/15/2024	NON-COMPETING CONTINUATION	-$231,174
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $371,340 )
2024	2024	METHODIST HOSPITAL, THE	6670 BERTNER AVE	HOUSTON	TX	77030	HARRIS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	5	5/3/2024	NON-COMPETING CONTINUATION	$26,799
2024	2024	METHODIST HOSPITAL, THE	6670 BERTNER AVE	HOUSTON	TX	77030	HARRIS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	12/28/2023	NON-COMPETING CONTINUATION	$344,541
														Subtotal = $371,340

Issue Date FY: 2023 ( Subtotal = $398,199 )
2023	2023	METHODIST HOSPITAL, THE	6670 BERTNER AVE	HOUSTON	TX	77030	HARRIS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	4	2/21/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$398,199
2023	2022	WAYNE STATE UNIVERSITY	5057 WOODWARD STE 13001	DETROIT	MI	48202	WAYNE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	2/20/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $398,199

Issue Date FY: 2022 ( Subtotal = $367,728 )
2022	2022	WAYNE STATE UNIVERSITY	5057 WOODWARD STE 13001	DETROIT	MI	48202	WAYNE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	3	3/27/2022	NON-COMPETING CONTINUATION	$36,773
2022	2022	WAYNE STATE UNIVERSITY	5057 WOODWARD STE 13001	DETROIT	MI	48202	WAYNE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	1/19/2022	NON-COMPETING CONTINUATION	$330,955
														Subtotal = $367,728

Issue Date FY: 2021 ( Subtotal = $367,728 )
2021	2021	WAYNE STATE UNIVERSITY	5057 WOODWARD STE 13001	DETROIT	MI	48202	WAYNE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	1/28/2021	NON-COMPETING CONTINUATION	$367,728
														Subtotal = $367,728

Issue Date FY: 2020 ( Subtotal = $380,418 )
2020	2020	WAYNE STATE UNIVERSITY	5057 WOODWARD STE 13001	DETROIT	MI	48202	WAYNE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	3/6/2020	NEW	$380,418
														Subtotal = $380,418

Grand Total All Awards = $1,885,413

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Myelin Junction Therapy in Peripheral Neuropathies

Award Number: R01NS115748

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: 03/15/2020

PERIOD OF PERFORMANCE END DATE: 12/31/2024

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