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Mitochondrial regulation of chemotherapy-induced reactive myelopoiesis and pro-metastatic effects

Award Number: R21CA288604
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/01/2025
PERIOD OF PERFORMANCE END DATE: 03/31/2027

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Mitochondrial regulation of chemotherapy-induced reactive myelopoiesis and pro-metastatic effects - Recent studies and our preliminary data highlight the importance of myelopoiesis in the chemotherapy induced accumulation of immunosuppressive myeloid cells. Growing evidence also demonstrates the ability of hematopoietic stem and progenitor cells (HSPCs) to sense inflammation, ultimately regulating HSPC proliferation and differentiation via metabolic alterations. It’s known that mitochondrial oxidative phosphorylation (OXPHOS) results in an increase of reactive oxygen species (ROS) production in HSPCs. However, our understanding of inflammation, metabolic alterations of HSPCs, and monocyte development is still limited. Current antioxidant strategies are not clinically effective. Finding novel targets could provide better therapeutic efficacy for combination therapy with chemotherapy. Mitochondria are the main source of ROS and are highly dynamic through the fission and fusion events, and dynamin-related protein 1 (Drp1) is an essential mediator of mitochondrial fission that elicits excessive ROS production. Importantly, targeting of excessive mitochondrial fission can regulate hematopoiesis via the mechanisms beyond ROS. The objective of this project is to determine whether mitochondrial ROS and Drp1 mediated HSPC mitochondria fission control chemotherapy induced reactive myelopoiesis and pro-metastatic effect. We hypothesize that chemotherapy induces reactive myelopoiesis by enhanced ROS production and Drp1- mediated mitochondrial fission in HSPCs, which drive the expansion of pro-metastatic monocytes. Further, targeting of mtROS or Drp1 reduces chemotherapy-induced metastases by regulating reactive myelopoiesis and monocyte phenotype. We will test our hypothesis by completing the following two specific aims: (1) Determine chemotherapy induced mitochondrial metabolism in HSPCs and phenotypic changes of monocytes, and (2) Determine whether targeting of Drp1 dependent mitochondrial fission reduces chemotherapy induced pro-metastatic effect. The proposed study is significant, because it will reveal a novel mechanism by which chemotherapy induces HSPC mitochondrial fission leading reactive myelopoiesis and pro-metastatic monocyte development. The discovery of role for mitochondrial fission in HSPCs after chemotherapy will stimulate new approach to improve anti-tumor efficacy of conventional chemotherapy.


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 = $183,494 )
2026	2026	UNIVERSITY OF LOUISVILLE	2301 S 3RD ST	LOUISVILLE	KY	40208	JEFFERSON	USA	Cancer Treatment Research	000	2	3/25/2026	NON-COMPETING CONTINUATION	$183,494
														Subtotal = $183,494

Issue Date FY: 2025 ( Subtotal = $220,018 )
2025	2025	UNIVERSITY OF LOUISVILLE	2301 S 3RD ST	LOUISVILLE	KY	40208	JEFFERSON	USA	Cancer Treatment Research	000	1	3/25/2025	NEW	$220,018
														Subtotal = $220,018

Grand Total All Awards = $403,512

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Mitochondrial regulation of chemotherapy-induced reactive myelopoiesis and pro-metastatic effects

Award Number: R21CA288604

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 04/01/2025

PERIOD OF PERFORMANCE END DATE: 03/31/2027

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