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Investigating the Cell Type- and Receptor-Specific Effects of Erythropoietin that Mediate Erythropoiesis and Thrombopoiesis in Primary Human Hematopoietic Progenitor Cells

Award Number: R03DK135896
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Investigating the Cell Type- and Receptor-Specific Effects of Erythropoietin that Mediate Erythropoiesis and Thrombopoiesis in Primary Human Hematopoietic Progenitor Cells - Chronic kidney disease (CKD) affects 37 million adults in the United States and results in anemia in more than 5 million patients. Patients with anemia due to CKD often require transfusion or pharmaceutical intervention to combat fatigue and hypoxia. The most common pharmaceutical intervention is injection of Erythropoietin (EPO), a cytokine that is produced in the healthy kidney in response to hypoxia. EPO promotes erythropoiesis by enhancing the survival and proliferation of erythroid-committed progenitors in the bone marrow. However, pharmaceutical EPO administration can cause thrombocytosis with an increased risk of stroke. This off-target consequence highlights an understudied role for EPO in non-erythroid-committed cell types and emphasizes the need for further research to clarify the effect of EPO on hematopoietic progenitors such as the Megakaryocytic-Erythroid bipotent progenitor and Megakaryocytic-committed progenitor. Furthermore, the receptors and downstream signaling pathways activated by EPO have not been fully elucidated in subpopulations of hematopoietic progenitors. Our preliminary results indicate that EPO supports survival and self-renewal of MEP. The research proposed in this application will investigate the cell-autonomous effects of EPO on bipotent human Megakaryocytic-Erythroid progenitors, Megakaryocytic-committed progenitors, and Erythroid- committed progenitors ex vivo by measuring activation of signaling mediators, transcriptional expression, and phenotypic changes. It will also clarify the receptors and targets that are activated in response to EPO signaling in defined hematopoietic subpopulations utilizing novel receptor-specific EPO mimetics. We hypothesize that in response to EPO, Megakaryocytic-Erythroid progenitors expand to increase the pool of progenitors capable of giving rise to erythroid and platelet-producing megakaryocytes, resulting in increased production of both platelets and red blood cells. Successful completion of these studies will resolve the molecular mechanism of the action of EPO on specific populations of cells in the bone marrow, which will aid in the development of more targeted and effective therapies for patients with chronic anemia.


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 = $184,150 )
2025	2025	UNIVERSITY OF CONNECTICUT HEALTH CENTER	263 FARMINGTON AVE	FARMINGTON	CT	06030	CAPITOL	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	2	11/20/2024	SUPPLEMENT FOR EXPANSION	$71,762
2025	2025	UNIVERSITY OF CONNECTICUT HEALTH CENTER	263 FARMINGTON AVE	FARMINGTON	CT	06030	CAPITOL	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	11/19/2024	NON-COMPETING CONTINUATION	$112,388
														Subtotal = $184,150

Issue Date FY: 2024 ( Subtotal = $166,488 )
2024	2024	UNIVERSITY OF CONNECTICUT HEALTH CENTER	263 FARMINGTON AVE	FARMINGTON	CT	06030	CAPITOL	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	12/6/2023	NEW	$124,656
2024	2024	UNIVERSITY OF CONNECTICUT HEALTH CENTER	263 FARMINGTON AVE	FARMINGTON	CT	06030	CAPITOL	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	1	5/7/2024	SUPPLEMENT FOR EXPANSION	$41,832
														Subtotal = $166,488

Grand Total All Awards = $350,638

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Investigating the Cell Type- and Receptor-Specific Effects of Erythropoietin that Mediate Erythropoiesis and Thrombopoiesis in Primary Human Hematopoietic Progenitor Cells

Award Number: R03DK135896

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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