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Coordinate regulation of erythroid and macrophage lineages in development by EKLF/KLF1

Award Number: R01DK121671
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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SUMMARY Erythroid cells mature in vivo in the presence of a supportive macrophage; this cell-cell compartment is known as the erythroblastic island, an entity first described over 50 years ago. Red cell interactions with the macrophage are critical for optimal nutrient access, survival, proliferation, and differentiation of the erythron. Our proposed experiments address the exciting idea that Erythroid Krüppel-like Factor (EKLF; KLF1) not only plays an intrinsic role in establishing the proper gene expression patterns in the red cell within the erythroblastic island, but that it additionally affects this process by an extrinsic mechanism based on its surprising expression within the island macrophage and early in development within the erythro-myeloid progenitor (EMP). Our studies build on observations made in primary or minimally manipulated cells, aided by in vivo assays and EKLF rescue systems. We have found that EKLF is expressed in the EMP in the yolk sac by E8.5. The experiments of Aim 1 will investigate the role of EKLF in directing the functional potential of these cells at later stages in the embryo and in the adult. We have found that macrophage-restricted ablation of EKLF extrinsically affects the red cell. The experiments of Aim 2 will examine an iron-related hypothesis for the red cell effect that may be important for stress recovery. We have found that fetal liver island macrophage display a unique gene expression signature that is extensively regulated by EKLF. The experiments of Aim 3 will assess EKLF's role in island macrophage identity, studies that will be extended to analysis of human cells. Understanding these basic mechanisms will ultimately aid in understanding the problems that arise in anemias that present with high levels of nucleated red blood cells in circulation, such as congenital dyserythropoietic anemia (CDA) type IV, and in the design of culture systems that enable efficient expansion and enucleation of human cell sources for clinical use.


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: 2023 ( Subtotal = $486,776 )
2023	2023	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	ONE GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	1/25/2023	NON-COMPETING CONTINUATION	$486,776
														Subtotal = $486,776

Issue Date FY: 2022 ( Subtotal = $486,775 )
2022	2022	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	ONE GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	1/21/2022	NON-COMPETING CONTINUATION	$438,096
2022	2022	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	ONE GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	3	4/1/2022	NON-COMPETING CONTINUATION	$48,679
														Subtotal = $486,775

Issue Date FY: 2021 ( Subtotal = $486,775 )
2021	2021	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	ONE GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	2/10/2021	NON-COMPETING CONTINUATION	$486,775
														Subtotal = $486,775

Issue Date FY: 2020 ( Subtotal = $465,752 )
2020	2020	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	ONE GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	4/13/2020	NEW	$465,752
														Subtotal = $465,752

Grand Total All Awards = $1,926,078

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Coordinate regulation of erythroid and macrophage lineages in development by EKLF/KLF1

Award Number: R01DK121671

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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