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Metabolic Regulation of erythropoiesis

Award Number: R01DK138865
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: 08/15/2023
PERIOD OF PERFORMANCE END DATE: 07/31/2026

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Metabolic Regulation of erythropoiesis - (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. Anemia is a common condition that causes significant morbidity and mortality and has a negative impact on quality of life. Although anemia can be caused by intrinsic defects in erythroid progenitor cells, the most common forms of anemia are extrinsic defects that affect erythropoiesis. After iron deficiency anemia, the anemia of inflammation is the second most common form of anemia. Inflammation caused by tissue damage or infection alters bone marrow hematopoiesis, skewing production towards myeloid cells at the expense of steady state erythropoiesis. This loss of erythroid output is compensated by stress erythropoiesis. Stress erythropoiesis is highly conserved between mouse and human. Unlike steady state erythropoiesis, which relies on constant production, stress erythropoiesis generates a bolus of new erythrocytes that maintain homeostasis until the source of the inflammation can be resolved. Like other stem cell-based tissue regeneration systems, stress erythropoiesis generates a transient amplifying population of immature stress erythroid progenitors (TA-SEPs), which then transition to a population of committed erythroid progenitors that differentiate into erythrocytes. The expansion of the TA population of SEPs represents a key stage in stress erythropoiesis. If too few TA-SEPs are generated, the subsequent production of erythrocytes will not be sufficient to maintain homeostasis. This proposal will address an outstanding question in this process. What mechanisms drove the proliferation of TA-SEPs during this critical period. Our previous work showed that TA-SEPs adopt a proliferative metabolism characterized by glycolysis and the shuttling of glycolytic metabolites into the anabolic pathways. The establishment of this metabolism requires nitric oxide, NO, dependent signaling. Inhibition of NO production blocks proliferation of TA-SEPs and slows recovery in a murine model of inflammatory anemia. In addition to NO, our data show that Wnt/b-catenin and Yap1 signaling are required for the proliferation TA-SEPs. In this proposal, we will address in two aims the mechanisms that regulate this proliferative metabolism. In Aim 1, we will address the role of NO dependent signaling in regulating the activity of key glycolytic enzymes, pyruvate kinase M2 and phosphofructo-2-kinase/Fructose 2,6-bisphosphatase 4 in TA-SEPs. In Aim 2, we will address the role of NO, Wnt and Yap1 in regulating glutamine metabolism.


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 = $306,898 )
2025	2025	THE PENNSYLVANIA STATE UNIVERSITY	201 OLD MAIN	UNIVERSITY PARK	PA	16802	CENTRE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	6	8/4/2025	NON-COMPETING CONTINUATION	$306,898
														Subtotal = $306,898

Issue Date FY: 2024 ( Subtotal = $304,057 )
2024	2024	THE PENNSYLVANIA STATE UNIVERSITY	201 OLD MAIN	UNIVERSITY PARK	PA	16802	CENTRE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	5	8/21/2024	NON-COMPETING CONTINUATION	$299,011
2024	2023	THE PENNSYLVANIA STATE UNIVERSITY	201 OLD MAIN	UNIVERSITY PARK	PA	16802	CENTRE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	8/13/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$5,046
														Subtotal = $304,057

Issue Date FY: 2023 ( Subtotal = $315,960 )
2023	2023	PENNSYLVANIA STATE UNIVERSITY, THE	201 OLD MAIN	UNIVERSITY PARK	PA	16802	CENTRE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	8/8/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$315,960
														Subtotal = $315,960

Grand Total All Awards = $926,915

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Metabolic Regulation of erythropoiesis

Award Number: R01DK138865

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: 08/15/2023

PERIOD OF PERFORMANCE END DATE: 07/31/2026

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