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Mitochondria mediated intercellular metabolic coupling in bone marrow regeneration

Award Number: R01DK124115
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/01/2024
PERIOD OF PERFORMANCE END DATE: 08/31/2025

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Mitochondria mediated intercellular metabolic coupling in bone marrow regeneration - (PLEASE KEEP IN WORD, DO NOT PDF) Enter the text here that is the new abstract information for your application. This section must be no longer than 30 lines of text. Hematopoietic stem cell (HSC) transplantation (HSCT) after conditioning is widely used in the clinic to treat pathological mutations in the lympho-hematopoietic system. The mechanisms on how the bone marrow (BM) microenvironment (ME) and transplanted HSC interact remains a mystery in biology. Understanding the underpinning mechanisms controlling mesenchymal BM-ME and HSC is arguably a major area of interest to optimize HSCT and generate optimal HSCT protocols that result in complete hematopoietic chimerism in the host with minimal or no myeloablative conditioning therapy. Our published data indicate that mesenchymal-lineage MSC undergo massive damage to their mitochondrial function following irradiation. Donor healthy HSPC transfer functional mitochondria to the stromal ME, thus improving mitochondria activity in recipient MSC. Mitochondrial transfer to the mesenchymal-lineage MSC is cell-contact dependent, positively regulated by mitochondrial connexin-43 (Cx43) and negatively regulated by cytosolic adenosine monophosphate kinase activity. In this proposal, we hypothesize that mitochondrial transfer from HSPC to BM stroma depends on the activity of Cx43 to control mitochondrial dynamics and downstream mitotransfer and is required for hematopoietic recovery during BM regeneration. The goal of this proposal is to identify the mechanisms by which Cx43 controls HSC mitochondrial dynamics and elucidate in detail the cellular and molecular mechanisms of mitochondria transfer from HSPC to BM MSC. We will identify the mechanisms by which Cx43 controls mitotransfer and regeneration and the role of mitochondrial Cx43 functional domains in mitochondrial dynamics, mitotransfer and hematopoietic regeneration. This proposal is the continuation and natural consequence of the NIDDK R01 DK124115 designed to start the exploration of the role of Cx43 as a regulator of hematopoietic metabolism and regeneration.


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: 2026 ( Subtotal = $0 )
2026	2024	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	11/20/2025	COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $150,000 )
2024	2024	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	4	8/20/2024	COMPETING CONTINUATION	$150,000
2024	2022	CHILDRENS HOSPITAL MEDICAL CENTER	3333 BURNET AVE	CINCINNATI	OH	45229	HAMILTON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	12/27/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $150,000

Issue Date FY: 2022 ( Subtotal = $279,840 )
2022	2022	CHILDREN'S HOSPITAL MEDICAL CENTER	3333 BURNET AVE	CINCINNATI	OH	45229	HAMILTON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	4/21/2022	NON-COMPETING CONTINUATION	$279,840
														Subtotal = $279,840

Issue Date FY: 2021 ( Subtotal = $279,840 )
2021	2021	CHILDREN'S HOSPITAL MEDICAL CENTER	3333 BURNET AVE	CINCINNATI	OH	45229	HAMILTON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	5/3/2021	NON-COMPETING CONTINUATION	$279,840
														Subtotal = $279,840

Issue Date FY: 2020 ( Subtotal = $279,840 )
2020	2020	CHILDREN'S HOSPITAL MEDICAL CENTER	3333 BURNET AVE	CINCINNATI	OH	45229	HAMILTON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	6/19/2020	NEW	$279,840
														Subtotal = $279,840

Grand Total All Awards = $989,520

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Mitochondria mediated intercellular metabolic coupling in bone marrow regeneration

Award Number: R01DK124115

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 09/01/2024

PERIOD OF PERFORMANCE END DATE: 08/31/2025

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