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Manipulation of MHC expression using TGF-beta2 to reduce mesenchymal stem cell immunogenicity

Award Number: K01OD027037
ORGANIZATION: OFFICE OF THE DIRECTOR, NIH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 12/15/2019
PERIOD OF PERFORMANCE END DATE: 11/30/2025

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Manipulation of MHC expression using TGF-beta2 to reduce mesenchymal stem cell immunogenicity - PROJECT SUMMARY/ABSTRACT The proposed Mentored Research Scientist Development Award (K01) will provide the candidate, Dr. Alix Berglund, DVM, PhD, with the necessary knowledge, training, and experience to become an independent translational biomedical researcher in the fields of immunology and mesenchymal stem cell (MSC) biology. MSCs are a promising cell source for treating inflammatory and immune-mediated diseases. Allogeneic therapy would provide cost-effective and efficient treatment, but is currently hindered by recipient immune rejection of donor MSCs expressing mismatched-major histocompatibility complex (MHC) molecules. MSCs are strongly immunomodulatory, however, and manipulation of MHC expression may be sufficient to allow donor MSCs to evade recipient immune responses. The central hypothesis of this proposal, which is supported by strong preliminary research, is that treating MSCs with transforming growth factor-β2 (TGF-β2) downregulates MHC I and MHC II gene transcription thereby reducing the in vivo immunogenicity of MHC-mismatched MSCs. The aims of this project are to 1) Identify how TGF-β2 downregulates MHC expression in MSCs and 2) Determine how TGF-β2 treatment affects MSC immunogenicity in vivo. Both murine and equine MSCs will be utilized to elucidate TGF-β2 signaling pathways to increase translational potential to humans (Aim 1) and non-inflammatory and inflammatory murine models will be used to analyze how the immune system responds to TGF-β2-treated MSCs in vivo (Aim 2). Completion of the proposed research is a first step towards improving the efficacy and safety of allogeneic MSCs for clinical use. To accomplish these aims, Dr. Berglund will build on her background in mesenchymal stem cell biology, immunology, and large animal models by developing expertise in molecular immunology techniques, in vivo alloimmune response analysis, and the utilization of murine models. Dr. Berglund's mentoring team has combined expertise in immunology, mesenchymal stem cells, and genetics to facilitate her transition to an independent translational biomedical researcher. This work will be completed primarily at the North Carolina State University College of Veterinary Medicine, which is eminently qualified to train translational clinician scientists, with additional work at the University of North Carolina-Chapel Hill.


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 = $127,467 )
2024	2024	UNIVERSITY OF MARYLAND, COLLEGE PARK	3112 LEE BUILDING	COLLEGE PARK	MD	20742	PRINCE GEORGES	USA	Research Infrastructure Programs	003	5	3/25/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$70,620
2024	2024	UNIVERSITY OF MARYLAND, COLLEGE PARK	3112 LEE BLDG 7809 REGENTS DR	COLLEGE PARK	MD	20742	PRINCE GEORGES	USA	Research Infrastructure Programs	001	5	12/6/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$127,467
2024	2023	NORTH CAROLINA STATE UNIVERSITY	2601 WOLF VILLAGE WAY	RALEIGH	NC	27695	WAKE	USA	Research Infrastructure Programs	002	4	3/25/2024	NON-COMPETING CONTINUATION	-$70,620
2024	2023	NORTH CAROLINA STATE UNIVERSITY	2601 WOLF VILLAGE WAY	RALEIGH	NC	27695	WAKE	USA	Research Infrastructure Programs	000	4	12/6/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $127,467

Issue Date FY: 2023 ( Subtotal = $130,990 )
2023	2023	NORTH CAROLINA STATE UNIVERSITY	2601 WOLF VILLAGE WAY	RALEIGH	NC	27607	WAKE	USA	Research Infrastructure Programs	000	4	11/30/2022	NON-COMPETING CONTINUATION	$130,990
														Subtotal = $130,990

Issue Date FY: 2022 ( Subtotal = $130,990 )
2022	2022	NORTH CAROLINA STATE UNIVERSITY	2601 WOLF VILLAGE WAY	RALEIGH	NC	27607	WAKE	USA	Research Infrastructure Programs	001	3	5/17/2022	NON-COMPETING CONTINUATION	$13,100
2022	2022	NORTH CAROLINA STATE UNIVERSITY	2601 WOLF VILLAGE WAY	RALEIGH	NC	27607	WAKE	USA	Research Infrastructure Programs	000	3	11/30/2021	NON-COMPETING CONTINUATION	$117,890
														Subtotal = $130,990

Issue Date FY: 2021 ( Subtotal = $130,990 )
2021	2021	NORTH CAROLINA STATE UNIVERSITY	2601 WOLF VILLAGE WAY	RALEIGH	NC	27607	WAKE	USA	Research Infrastructure Programs	001	2	3/12/2021	NON-COMPETING CONTINUATION	$13,100
2021	2021	NORTH CAROLINA STATE UNIVERSITY	2601 WOLF VILLAGE WAY	RALEIGH	NC	27607	WAKE	USA	Research Infrastructure Programs	000	2	11/12/2020	NON-COMPETING CONTINUATION	$117,890
														Subtotal = $130,990

Issue Date FY: 2020 ( Subtotal = $130,990 )
2020	2020	NORTH CAROLINA STATE UNIVERSITY	2701 SULLIVAN DR STE 240	RALEIGH	NC	27695	WAKE	USA	Research Infrastructure Programs	000	1	12/5/2019	NEW	$117,891
2020	2020	NORTH CAROLINA STATE UNIVERSITY	2701 SULLIVAN DR STE 240	RALEIGH	NC	27695	WAKE	USA	Research Infrastructure Programs	001	1	4/22/2020	NEW	$13,099
														Subtotal = $130,990

Grand Total All Awards = $651,427

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Manipulation of MHC expression using TGF-beta2 to reduce mesenchymal stem cell immunogenicity

Award Number: K01OD027037

ORGANIZATION: OFFICE OF THE DIRECTOR, NIH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 12/15/2019

PERIOD OF PERFORMANCE END DATE: 11/30/2025

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