Sunday, November 24, 2024 11/24/2024

Mechanism of the short- and long-term effects of COVID-19-induced Alarmins on hematopoietic stem and progenitor cells.

Award Number: R01DK130478
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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ABSTRACT The long-term goal of this proposal is to understand the long-term sequalae of acute COVID-19 infection on hematopoietic and immune damages, and to identify the key pathways and mechanism by which COVID-19- associated cytokine dysregulation alters HSC function and differentiation. SARS-CoV-2 infection causes local and systemic damages due to dysregulated immune response and cytokine production. Its long-term negative effects on body tissue and organ remain largely unknown. Our published work showed that SARS-CoV-2 infection dramatically increased neutrophil production and neutrophil-associated S100A8/A9 (Alarmin) release. Persistent high level of S100A8/A9 is a negative prognostic biomarker for the disease severity and mortality. Although the function of S100A8/A9 on mature blood cells have been studied, its functional effect on hematopoietic stem cells (HSCs) are unknown. Our preliminary data show that S100A8/A9 causes loss of quiescence and differentiation of HSC toward myeloid progenitors at the expense of HSCs. Toll-like receptor 4 (TLR4), the endogenous receptor of S100A8/A9, is highly expressed in HSCs, and S100A8/A9 activates its canonical downstream MAPK (mitogen-activated protein kinase) pathway. Very interestingly, S100A8/A9 causes downregulation of epigenetic regulator Setd2, leading to the c-Myc upregulation in HSCs. c-Myc is a key downstream target of both MAPK and Setd2 pathways. MAPK, Setd2 and c-Myc are important regulators of HSC proliferation and myeloid differentiation. We hypothesize that SARS-CoV-2-induced S100A8/A9 activates TLR4 signaling which converts to c-Myc in HSCs, resulting in loss of quiescence and self-renewal, myeloid differentiation skewing, and long-term impairment of hematopoiesis. Since HSC is responsible for the life-long production of blood cells, including all types of immune cells, any functional damages of HSCs would later on have profoundly negative effects on the immune response. Therefore, understanding the cellular and molecular mechanism by which S100A8/A9 regulates HSCs and hematopoiesis would contribute a new evidence base to accelerate advances in diagnostics, therapeutics, clinical management of COVID-19 patients in acute infection and recovery phases. 1


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: 2024 ( Subtotal = $0 )
2024	2023	NEW YORK BLOOD CENTER, INC	310 E 67TH ST	NEW YORK	NY	10065	NEW YORK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	3	11/6/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$73,977
2024	2022	UNIVERSITY OF KENTUCKY RESEARCH FOUNDATION, THE	500 S LIMESTONE	LEXINGTON	KY	40526	FAYETTE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	11/6/2023	NON-COMPETING CONTINUATION	-$73,977
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $435,732 )
2023	2023	NEW YORK BLOOD CENTER, INC.	310 E 67TH ST	NEW YORK	NY	10065	NEW YORK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	3	7/19/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$435,732
2023	2022	UNIVERSITY OF KENTUCKY RESEARCH FOUNDATION, THE	500 S LIMESTONE 109 KINKEAD HALL	LEXINGTON	KY	40526	FAYETTE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	7/18/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $435,732

Issue Date FY: 2022 ( Subtotal = $388,500 )
2022	2022	UNIVERSITY OF KENTUCKY RESEARCH FOUNDATION, THE	500 S LIMESTONE 109 KINKEAD HALL	LEXINGTON	KY	40526	FAYETTE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	7/5/2022	NON-COMPETING CONTINUATION	$388,500
														Subtotal = $388,500

Issue Date FY: 2021 ( Subtotal = $401,750 )
2021	2021	UNIVERSITY OF KENTUCKY	500 S LIMESTONE 109 KINKEAD HALL	LEXINGTON	KY	40526	FAYETTE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	8/17/2021	NEW	$401,750
														Subtotal = $401,750

Grand Total All Awards = $1,225,982

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Mechanism of the short- and long-term effects of COVID-19-induced Alarmins on hematopoietic stem and progenitor cells.

Award Number: R01DK130478

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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