Thursday, November 21, 2024 11/21/2024

Carbohydrate-Mediated Platelet Clearance

Award Number: R01HL089224
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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ABSTRACT Maintenance of normal hematopoiesis depends on developmental programs for the hematopoietic stem and progenitor cell (HSPC). Still, these programs require guidance by cell-extrinsic mechanisms that correctly convey the dynamically changing needs of the blood cells. Our prior work established that the hepatocyte-specific Ashwell-Morell receptor (AMR), a multimeric endocytic receptor, binds to aged platelets, inducing JAK-STAT signaling and production of thrombopoietin (TPO), the cytokine responsible for megakaryocyte maturation and differentiation, platelet production, and maintenance of HSPCs. In addition to regulating TPO production and removing aged platelets, we uncovered an unexpected mechanism by which the AMR regulates erythropoiesis. Our preliminary data suggest a role for the hepatic AMR in regulating Neuregulin 4 (Nrg4) levels, the specific ligand for ErbB4 (also known as HER4), the fourth member of the receptor tyrosine kinase family that includes the epidermal growth factor (EGF) receptor (EGFR/HER1), ErbB2/HER2, and ErbB3/HER3. A genome-wide association study (GWAS) shows that NRG4 variants are associated with changes in hemoglobin levels, and ErbB4 signaling contributes to human and mouse erythropoiesis. Our data shows that an increase in Nrg4 affects ErbB4 expression and signaling in bone marrow mesenchymal stem cells (MSCs), leading to defective erythropoiesis and increased expression levels of S100a8 and S100a9, members of the calcium-binding S100 protein family, known as Calgranulin A and B, respectively. Recombinant, extracellular, and increased S100a8 expression levels in erythrocyte progenitors induce an erythroid differentiation defect. We seek to define how Nrg4/ErbB4 affects HSPC homeostasis and erythropoiesis, including erythroblastic islands (Aim 1). We will interrogate the mechanism by which Nrg4/ErbB4 affect MSC function, calgranulin expression, and erythropoiesis (Aim 2). We use a multipronged approach of genetic mouse modeling, inhibitors, transcriptomics, and biochemical approaches to allow mechanistic exploration into the participation of the Nrg4/ErbB4/calgranulin axis in contributing to erythropoiesis. The proposed investigation will further drive therapeutic development to ameliorate erythropoietic deficiencies in blood disease, including in patients with myeloproliferative neoplasms and myelodysplastic syndrome.


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 = $626,995 )
2024	2024	VERSITI WISCONSIN, INC.	638 N 18TH ST	MILWAUKEE	WI	53233	MILWAUKEE	USA	Blood Diseases and Resources Research	001	16	6/14/2024	NON-COMPETING CONTINUATION	$46,394
2024	2024	VERSITI WISCONSIN, INC.	638 N 18TH ST	MILWAUKEE	WI	53233	MILWAUKEE	USA	Blood Diseases and Resources Research	000	16	1/23/2024	NON-COMPETING CONTINUATION	$521,930
2024	2024	VERSITI WISCONSIN, INC.	638 N 18TH ST	MILWAUKEE	WI	53233	MILWAUKEE	USA	Blood Diseases and Resources Research	005	16	9/19/2024	SUPPLEMENT FOR EXPANSION	$90,453
2024	2023	VERSITI WISCONSIN, INC.	638 N 18TH ST	MILWAUKEE	WI	53233	MILWAUKEE	USA	Blood Diseases and Resources Research	003	15	7/25/2024	COMPETING CONTINUATION	$12,114
2024	2020	VERSITI WISCONSIN, INC.	638 N 18TH ST	MILWAUKEE	WI	53233	MILWAUKEE	USA	Blood Diseases and Resources Research	004	14	8/13/2024	SUPPLEMENT FOR EXPANSION	-$31,782
2024	2020	VERSITI WISCONSIN, INC.	638 N 18TH ST	MILWAUKEE	WI	53233	MILWAUKEE	USA	Blood Diseases and Resources Research	002	14	7/25/2024	NON-COMPETING CONTINUATION	-$12,114
														Subtotal = $626,995

Issue Date FY: 2023 ( Subtotal = $516,972 )
2023	2023	VERSITI WISCONSIN, INC.	638 N 18TH ST	MILWAUKEE	WI	53233	MILWAUKEE	USA	Blood Diseases and Resources Research	000	15	1/16/2023	COMPETING CONTINUATION	$516,972
														Subtotal = $516,972

Issue Date FY: 2022 ( Subtotal = $0 )
2022	2020	VERSITI WISCONSIN, INC.	638 N 18TH ST	MILWAUKEE	WI	53233	MILWAUKEE	USA	Blood Diseases and Resources Research	001	14	11/24/2021	SUPPLEMENT FOR EXPANSION	$0
2022	2020	VERSITI WISCONSIN, INC.	638 N 18TH ST	MILWAUKEE	WI	53233	MILWAUKEE	USA	Blood Diseases and Resources Research	000	14	11/22/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2020 ( Subtotal = $1,131,900 )
2020	2020	VERSITI WISCONSIN, INC.	638 N 18TH ST	MILWAUKEE	WI	53233	MILWAUKEE	USA	Blood Diseases and Resources Research	002	14	8/6/2020	SUPPLEMENT FOR EXPANSION	$495,000
2020	2020	VERSITI WISCONSIN, INC.	638 N 18TH ST	MILWAUKEE	WI	53233	MILWAUKEE	USA	Blood Diseases and Resources Research	000	14	5/14/2020	NON-COMPETING CONTINUATION	$636,900
2020	2020	VERSITI WISCONSIN, INC.	638 N 18TH ST	MILWAUKEE	WI	53233	MILWAUKEE	USA	Blood Diseases and Resources Research	001	14	8/6/2020	NON-COMPETING CONTINUATION	$0
														Subtotal = $1,131,900

Issue Date FY: 2019 ( Subtotal = $723,928 )
2019	2019	VERSITI WISCONSIN, INC.	638 N 18TH ST	MILWAUKEE	WI	53233	MILWAUKEE	USA	Blood Diseases and Resources Research	000	13	5/22/2019	NON-COMPETING CONTINUATION	$654,455
2019	2017	VERSITI WISCONSIN, INC.	638 N 18TH ST	MILWAUKEE	WI	53233	MILWAUKEE	USA	Blood Diseases and Resources Research	001	11	9/3/2019	COMPETING CONTINUATION	$69,473
														Subtotal = $723,928

Issue Date FY: 2018 ( Subtotal = $562,019 )
2018	2018	BLOODCENTER OF WISCONSIN, INC.	638 N 18TH ST	MILWAUKEE	WI	53233	MILWAUKEE	USA	Blood Diseases and Resources Research	001	12	5/10/2018	NON-COMPETING CONTINUATION	$631,492
2018	2016	BLOODCENTER OF WISCONSIN, INC.	638 N 18TH ST	MILWAUKEE	WI	53233	MILWAUKEE	USA	Blood Diseases and Resources Research	000	10	1/8/2018	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	-$69,473
														Subtotal = $562,019

Issue Date FY: 2017 ( Subtotal = $618,132 )
2017	2017	BLOODCENTER OF WISCONSIN, INC.	638 N 18TH ST	MILWAUKEE	WI	53233	MILWAUKEE	USA	Blood Diseases and Resources Research	006	11	8/23/2017	COMPETING CONTINUATION	$0
2017	2017	BLOODCENTER OF WISCONSIN, INC.	638 N 18TH ST	MILWAUKEE	WI	53233	MILWAUKEE	USA	Blood Diseases and Resources Research	005	11	7/24/2017	COMPETING CONTINUATION	$618,132
2017	2016	BLOODCENTER OF WISCONSIN, INC.	638 N 18TH ST	MILWAUKEE	WI	53233	MILWAUKEE	USA	Blood Diseases and Resources Research	004	10	7/21/2017	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
2017	2016	BLOODCENTER OF WISCONSIN, INC.	638 N 18TH ST	MILWAUKEE	WI	53233	MILWAUKEE	USA	Blood Diseases and Resources Research	001	10	2/28/2017	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$319,500
2017	2016	BLOODCENTER OF WISCONSIN, INC.	638 N 18TH ST	MILWAUKEE	WI	53233	MILWAUKEE	USA	Blood Diseases and Resources Research	003	10	5/26/2017	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$26,203
2017	2016	BRIGHAM AND WOMEN'S HOSPITAL, INC., THE	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Blood Diseases and Resources Research	000	9	2/27/2017	EXTENSION WITH OR WITHOUT FUNDS	-$319,500
2017	2016	BRIGHAM AND WOMEN'S HOSPITAL, INC., THE	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Blood Diseases and Resources Research	002	9	5/26/2017	EXTENSION WITH OR WITHOUT FUNDS	-$26,203
														Subtotal = $618,132

Issue Date FY: 2016 ( Subtotal = $420,500 )
2016	2016	BRIGHAM & WOMEN`S HOSPITAL	10 VINING STREET	BOSTON	MA	02115	SUFFOLK	USA	Blood Diseases and Resources Research	000	9	3/1/2016	EXTENSION WITH OR WITHOUT FUNDS	$420,500
														Subtotal = $420,500

Issue Date FY: 2015 ( Subtotal = $413,650 )
2015	2015	BRIGHAM & WOMEN`S HOSPITAL	10 VINING STREET	BOSTON	MA	02115	SUFFOLK	USA	Blood Diseases and Resources Research	000	8	3/17/2015	NON-COMPETING CONTINUATION	$413,650
														Subtotal = $413,650

Issue Date FY: 2014 ( Subtotal = $410,473 )
2014	2014	BRIGHAM & WOMEN`S HOSPITAL	10 VINING STREET	BOSTON	MA	02115	SUFFOLK	USA	Blood Diseases and Resources Research	000	7	3/21/2014	NON-COMPETING CONTINUATION	$410,473
														Subtotal = $410,473

Issue Date FY: 2013 ( Subtotal = $397,698 )
2013	2013	BRIGHAM & WOMEN`S HOSPITAL	10 VINING STREET	BOSTON	MA	02115	SUFFOLK	USA	Blood Diseases and Resources Research	001	6	4/1/2013	COMPETING CONTINUATION	$375,975
2013	2013	BRIGHAM & WOMEN`S HOSPITAL	10 VINING STREET	BOSTON	MA	02115	SUFFOLK	USA	Blood Diseases and Resources Research	002	6	7/3/2013	COMPETING CONTINUATION	$21,723
2013	2011	BRIGHAM & WOMEN`S HOSPITAL	10 VINING STREET	BOSTON	MA	02115	SUFFOLK	USA	Blood Diseases and Resources Research	000	5	3/29/2013	NON-COMPETING CONTINUATION	$0
														Subtotal = $397,698

Issue Date FY: 2011 ( Subtotal = $410,264 )
2011	2011	BRIGHAM & WOMEN`S HOSPITAL	10 VINING STREET	BOSTON	MA	02115	SUFFOLK	USA	Blood Diseases and Resources Research	000	5	6/15/2011	NON-COMPETING CONTINUATION	$410,264
														Subtotal = $410,264

Issue Date FY: 2010 ( Subtotal = $411,057 )
2010	2010	BRIGHAM & WOMEN'S HOSPITAL	10 VINING STREET	BOSTON	MA	02115	SUFFOLK	USA	Blood Diseases and Resources Research	000	4	6/30/2010	NON-COMPETING CONTINUATION	$411,057
														Subtotal = $411,057

Issue Date FY: 2009 ( Subtotal = $686,772 )
2009	2009	BRIGHAM & WOMEN'S HOSPITAL	10 VINING STREET	BOSTON	MA	02115	SUFFOLK	USA	Trans-NIH Recovery Act Research Support	001	3	7/30/2009	SUPPLEMENT FOR EXPANSION	$274,944
2009	2009	BRIGHAM & WOMEN'S HOSPITAL	10 VINING STREET	BOSTON	MA	02115	SUFFOLK	USA	Blood Diseases and Resources Research	000	3	6/26/2009	NON-COMPETING CONTINUATION	$411,828
														Subtotal = $686,772

Issue Date FY: 2008 ( Subtotal = $412,575 )
2008	2008	BRIGHAM & WOMEN'S HOSPITAL	10 VINING STREET	BOSTON	MA	02115	SUFFOLK	USA	Blood Diseases and Resources Research	000	2	7/2/2008	NON-COMPETING CONTINUATION	$412,575
														Subtotal = $412,575

Issue Date FY: 2007 ( Subtotal = $413,301 ) (Continued on the next page)
Grand Total All Awards = $8,156,236

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Carbohydrate-Mediated Platelet Clearance

Award Number: R01HL089224

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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