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Stem Cell Surface Modification to Promote Nerve Regeneration

Award Number: R01NS117102
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: 01/15/2021
PERIOD OF PERFORMANCE END DATE: 12/31/2026

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Stem Cell Surface Modification to Promote Nerve Regeneration - Project Summary Peripheral nerve injury, especially critical-sized nerve gap injury, often results in poor recovery of function and impaired quality of life for the patient. Stem cell therapy holds significant promise; however, its clinical application has been largely hampered by limited stem cell adhesion and the lack of efficient differentiation. We have shown that our stem cell surface modification technique is able to profoundly influence specific cell-cell and cell-matrix interactions. Therefore, our specific aims are to develop and optimize novel candidate analogs to promote human adipose stem cell (hASC) adhesion and differentiation in vitro; to incorporate the cell surface modification technique into hASC-based therapies to improve peripheral nerve regeneration; and to investigate related mechanisms underlying improved nerve regeneration. Aim1: To develop and optimize novel analogs by metabolic glycoengineering (MGE) technology to promote hASC's cell adhesion and cell differentiation in vitro. We will optimize the cell surface modification with thiolated sugar analogs (ManNAc), evaluate the effects, and thoroughly characterize them to promote hASCs adhesion, proliferation, and differentiation. Aim2: To incorporate MGE into hASC-based therapies to improve peripheral nerve regeneration. With optimized ManNAc analogs, we will systemically evaluate the effect of glycoengineered hASCs on nerve regeneration after nerve repair and further optimize the therapy. Aim 3: To examine the mechanism by which thiol-derivatized ManNAc analogs contribute to nerve regeneration . With expected improvements in nerve regeneration, we will evaluate signaling pathways (e.g., Wnt / β after MGE'ed hASC transplantation. -catenin) modulated by MGE The innovation lies in our hypothesis to modify stem cell surface glycan properties with sugar analogs to improve cell survival and differentiation, our novel and effective technology, and the new application of these technologies in a fully translational nerve repair model to develop a novel treatment. The significance lies in the novel cell-based therapy with surface modification to address one of the most challenging aspects of nerve regeneration for critical-sized nerve gap repair, and the expected discovery of the mechanism underlying improved survival and differentiation by transplanted MGE'ed hASC. Our technology and protocols are highly translatable to the clinical environment. Success in this project will have direct translational implications for patients with peripheral nerve trauma requiring surgical repair. The clinical study of ManNAc has demonstrated the safety of single oral doses up to 6 g, and the FDA has approved the use of ManNAc to treat GNE Myopathy. Our study will lead to the development of novel therapeutic strategies for nerve repair that can contribute to future clinical interventions and maximize the benefits of stem cell therapy based on the new findings.


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 = $272,722 )
2025	2025	UNIVERSITY OF MARYLAND, BALTIMORE	220 ARCH ST OFC LEVEL2	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	3/11/2025	NON-COMPETING CONTINUATION	$272,722
														Subtotal = $272,722

Issue Date FY: 2024 ( Subtotal = $0 )
2024	2023	UNIVERSITY OF MARYLAND, BALTIMORE	220 ARCH ST OFC LEVEL2	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	5/7/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $429,960 )
2023	2023	UNIVERSITY OF MARYLAND	220 ARCH ST RM 02148	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	3	2/2/2023	NON-COMPETING CONTINUATION	$42,996
2023	2023	UNIVERSITY OF MARYLAND	220 ARCH ST RM 02148	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	12/29/2022	NON-COMPETING CONTINUATION	$386,964
														Subtotal = $429,960

Issue Date FY: 2022 ( Subtotal = $454,209 )
2022	2022	UNIVERSITY OF MARYLAND	220 ARCH ST RM 02148	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	12/21/2021	NON-COMPETING CONTINUATION	$408,788
2022	2022	UNIVERSITY OF MARYLAND	220 ARCH ST RM 02148	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	2	3/24/2022	NON-COMPETING CONTINUATION	$45,421
														Subtotal = $454,209

Issue Date FY: 2021 ( Subtotal = $461,021 )
2021	2021	UNIVERSITY OF MARYLAND	220 ARCH ST RM 02148	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	1/7/2021	NEW	$461,021
														Subtotal = $461,021

Grand Total All Awards = $1,617,912

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Stem Cell Surface Modification to Promote Nerve Regeneration

Award Number: R01NS117102

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: 01/15/2021

PERIOD OF PERFORMANCE END DATE: 12/31/2026

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