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EPO regulated erythropoiesis

Award Number: R01HL044491
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/25/2017
PERIOD OF PERFORMANCE END DATE: 02/28/2023

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EPO regulated erythropoiesis - DESCRIPTION (provided by applicant): Investigations of hematopoietic growth factor bio-effects and action mechanisms continue to provide important insight into (dys) regulated blood cell formation. The EPO receptor (EPOR) system is an informative and clinically significant paradigm. Recent studies applying contemporary approaches indicate major gaps in the field's understanding of EPO/EPOR/JAK2 signal transducers and their regulation of erythroid progenitor cell (EPC) formation. To illustrate, the PI has recently identified a novel EPOR/JAK2/STAT5 pathway in which an EPO-induced Spi2A serpin cytoprotects EPCs against executioner cathepsins as leached from ROS-compromised lysosomes [JEM 210:225-32]. And Dr. T. Ganz's laboratory has characterized an EPOR/JAK2/STAT5-induced "Erythroferrone" TNF cytokine as a hepcidin suppressor [Nat Genet. 46:678-84]. Via major supporting studies for this R01 renewal, we've applied post-translational modification (PTM) based LC-MS/MS proteomics to discover intriguing new mediators of EPO/EPOR/JAK2 action. These include 50+ factors not previously linked to EPO-dependent erythropoiesis within diverse functional categories of molecular adaptors, erythroid cytoskeletal proteins, kinases & phosphatases, and cell cycle & survival factors. SA#1 will extend our PTM-directed proteomic investigations in human erythroid precursor cells to include broad-based targets as modified at pY, T*PP and ubiquitin motifs, together with analyses of more select signaling nodes for S/T kinases, survival/apoptosis factors and cell cycle targets. Networks for hundreds of specifically activated PTM events for novel (and known) EPO targets and transducers will be mined (with collaborating expert bioinformaticists). SA#2 focuses on defining the functional roles and action mechanisms of three interrelated new EPO targets as upstream effectors of EPOR/JAK2 complexes. Two, C1ORF186/"RHEX" and C1ORF150, are novel molecular adaptors that have evolved as EPO signal transducers in hEPC's (but are absent among mice, rats, lower vertebrates). Third, PTPN18 is a protein tyrosine phosphatase which we demonstrate to increase JAK2 activation, decrease EPOR turnover and limit pY-RHEX formation. Approaches will include GOF, shRNA LOF, and mutant rescue studies in UT7epo cells and primary hEPCs. SA#3 then focuses on a new downstream mediator of EPO action, Thioredoxin-Interacting Protein (TXNIP). EPO modulates TXNIP at C-terminal pT/pS sites, and heightens its expression. TXNIP knockdown attenuates EPC growth, and notably accelerates primary erythroid precursor development to KIT-low, GPA-high hemoglobinizing erythroblasts. Mechanistically how TXNIP acts as a novel EPO agent will be determined by analyzing EPC growth, survival, ROS, miRNA populations and metabolic properties. Overall, studies will reveal important new mediators of EPO-dependent human erythropoiesis. Certain may be druggable with potentials to lessen EPO dosing, and limit EPO's major adverse side effects. Other new EPO targets may functionally relate to MPNs and/or to EPO's potential to worsen cancer outcomes.


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	2020	UNIVERSITY SYSTEM OF NEW HAMPSHIRE	51 COLLEGE RD	DURHAM	NH	03824	STRAFFORD	USA	Blood Diseases and Resources Research	000	23	12/6/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $0 )
2022	2020	UNIVERSITY SYSTEM OF NEW HAMPSHIRE	51 COLLEGE RD SERVICE BLDG 107	DURHAM	NH	03824	STRAFFORD	USA	Blood Diseases and Resources Research	000	23	2/11/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2020 ( Subtotal = $380,571 )
2020	2020	UNIVERSITY SYSTEM OF NEW HAMPSHIRE	51 COLLEGE RD SERVICE BLDG 107	DURHAM	NH	03824	STRAFFORD	USA	Blood Diseases and Resources Research	000	23	3/16/2020	NON-COMPETING CONTINUATION	$380,571
														Subtotal = $380,571

Issue Date FY: 2019 ( Subtotal = $380,571 )
2019	2019	UNIVERSITY SYSTEM OF NEW HAMPSHIRE	51 COLLEGE RD SERVICE BLDG 107	DURHAM	NH	03824	STRAFFORD	USA	Blood Diseases and Resources Research	000	22	3/18/2019	NON-COMPETING CONTINUATION	$380,571
														Subtotal = $380,571

Issue Date FY: 2018 ( Subtotal = $383,603 )
2018	2018	UNIVERSITY SYSTEM OF NEW HAMPSHIRE	51 COLLEGE RD SERVICE BLDG 107	DURHAM	NH	03824	STRAFFORD	USA	Blood Diseases and Resources Research	004	21	3/1/2018	NON-COMPETING CONTINUATION	$375,930
2018	2018	UNIVERSITY SYSTEM OF NEW HAMPSHIRE	51 COLLEGE RD SERVICE BLDG 107	DURHAM	NH	03824	STRAFFORD	USA	Blood Diseases and Resources Research	005	21	9/5/2018	NON-COMPETING CONTINUATION	$7,673
2018	2017	MAINE MEDICAL CENTER	22 BRAMHALL ST	PORTLAND	ME	04102	CUMBERLAND	USA	Blood Diseases and Resources Research	001	19	11/1/2017	NON-COMPETING CONTINUATION	-$43,497
2018	2017	UNIVERSITY SYSTEM OF NEW HAMPSHIRE	51 COLLEGE RD SERVICE BLDG 107	DURHAM	NH	03824	STRAFFORD	USA	Blood Diseases and Resources Research	002	20	11/1/2017	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$192,485
2018	2017	UNIVERSITY SYSTEM OF NEW HAMPSHIRE	51 COLLEGE RD SERVICE BLDG 107	DURHAM	NH	03824	STRAFFORD	USA	Blood Diseases and Resources Research	003	20	1/19/2018	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
2018	2016	MAINE MEDICAL CENTER	22 BRAMHALL ST	PORTLAND	ME	04102	CUMBERLAND	USA	Cardiovascular Diseases Research	000	18	11/1/2017	COMPETING CONTINUATION	-$148,988
														Subtotal = $383,603

Issue Date FY: 2017 ( Subtotal = $380,500 )
2017	2017	MAINE MEDICAL CENTER	22 BRAMHALL ST	PORTLAND	ME	04102	CUMBERLAND	USA	Blood Diseases and Resources Research	000	19	3/8/2017	NON-COMPETING CONTINUATION	$380,500
2017	2017	UNIVERSITY SYSTEM OF NEW HAMPSHIRE	51 COLLEGE RD SERVICE BLDG 107	DURHAM	NH	03824	STRAFFORD	USA	Blood Diseases and Resources Research	002	20	9/5/2017	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$337,003
2017	2017	MAINE MEDICAL CENTER	22 BRAMHALL ST	PORTLAND	ME	04102	CUMBERLAND	USA	Blood Diseases and Resources Research	001	19	9/4/2017	NON-COMPETING CONTINUATION	-$337,003
														Subtotal = $380,500

Issue Date FY: 2016 ( Subtotal = $408,500 )
2016	2016	MAINE MEDICAL CENTER	22 BRAMHALL STREET	PORTLAND	ME	04102	CUMBERLAND	USA	Cardiovascular Diseases Research	000	18	6/15/2016	COMPETING CONTINUATION	$408,500
														Subtotal = $408,500

Issue Date FY: 2014 ( Subtotal = $0 )
2014	2012	MAINE MEDICAL CENTER	22 BRAMHALL STREET	PORTLAND	ME	04102	CUMBERLAND	USA	Blood Diseases and Resources Research	000	17	3/31/2014	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2012 ( Subtotal = $372,488 )
2012	2012	MAINE MEDICAL CENTER	22 BRAMHALL STREET	PORTLAND	ME	04102	CUMBERLAND	USA	Blood Diseases and Resources Research	000	17	4/2/2012	NON-COMPETING CONTINUATION	$372,488
														Subtotal = $372,488

Issue Date FY: 2011 ( Subtotal = $376,250 )
2011	2011	MAINE MEDICAL CENTER	22 BRAMHALL STREET	PORTLAND	ME	04102	CUMBERLAND	USA	Blood Diseases and Resources Research	000	16	3/4/2011	NON-COMPETING CONTINUATION	$376,250
														Subtotal = $376,250

Issue Date FY: 2010 ( Subtotal = $376,250 )
2010	2010	MAINE MEDICAL CENTER	22 BRAMHALL STREET	PORTLAND	ME	04102	CUMBERLAND	USA	Blood Diseases and Resources Research	001	15	4/15/2010	NON-COMPETING CONTINUATION	$376,250
2010	2007	MAINE MEDICAL CENTER	22 BRAMHALL STREET	PORTLAND	ME	04102	CUMBERLAND	USA	Blood Diseases and Resources Research	000	13	2/5/2010	NON-COMPETING CONTINUATION	$0
														Subtotal = $376,250

Issue Date FY: 2009 ( Subtotal = $376,250 )
2009	2009	MAINE MEDICAL CENTER	22 BRAMHALL STREET	PORTLAND	ME	04102	CUMBERLAND	USA	Blood Diseases and Resources Research	001	14	4/9/2009	COMPETING CONTINUATION	$376,250
2009	2007	MAINE MEDICAL CENTER	22 BRAMHALL STREET	PORTLAND	ME	04102	CUMBERLAND	USA	Blood Diseases and Resources Research	000	13	11/26/2008	NON-COMPETING CONTINUATION	$0
														Subtotal = $376,250

Issue Date FY: 2007 ( Subtotal = $289,385 )
2007	2007	MAINE MEDICAL CENTER	22 BRAMHALL STREET	PORTLAND	ME	04102	CUMBERLAND	USA	Blood Diseases and Resources Research	000	13	1/13/2007	NON-COMPETING CONTINUATION	$289,385
														Subtotal = $289,385

Issue Date FY: 2006 ( Subtotal = $298,028 )
2006	2006	MAINE MEDICAL CENTER	22 BRAMHALL STREET	PORTLAND	ME	04102	CUMBERLAND	USA	Blood Diseases and Resources Research	000	12	12/27/2005	NON-COMPETING CONTINUATION	$298,028
														Subtotal = $298,028

Issue Date FY: 2005 ( Subtotal = $305,200 )
2005	2005	MAINE MEDICAL CENTER	22 BRAMHALL STREET	PORTLAND	ME	04102	CUMBERLAND	USA	Blood Diseases and Resources Research	000	11	1/5/2005	NON-COMPETING CONTINUATION	$305,200
														Subtotal = $305,200

Issue Date FY: 2004 ( Subtotal = $305,200 )
2004	2004	MAINE MEDICAL CENTER	22 BRAMHALL STREET	PORTLAND	ME	04102	CUMBERLAND	USA	Blood Diseases and Resources Research	000	10	1/19/2004	COMPETING CONTINUATION	$305,200
														Subtotal = $305,200

Issue Date FY: 2000 ( Subtotal = $175,340 )
2000	2000	PENNSYLVANIA STATE UNIVERSITY	110 TECHNOLOGY CENTER BUILDING	UNIVERSITY PARK	PA	16802	CENTRE	USA	Blood Diseases and Resources Research	000	9	8/14/2000	NON-COMPETING CONTINUATION	$175,340
														Subtotal = $175,340

Issue Date FY: 1999 ( Subtotal = $171,061 )
1999	1999	PENNSYLVANIA STATE UNIVERSITY	110 TECHNOLOGY CENTER BUILDING	UNIVERSITY PARK	PA	16802	CENTRE	USA	Blood Diseases and Resources Research	000	8	6/23/1999	NON-COMPETING CONTINUATION	$171,061
														Subtotal = $171,061

Issue Date FY: 1998 ( Subtotal = $152,702 )
1998	1998	PENNSYLVANIA STATE UNIVERSITY	110 TECHNOLOGY CENTER BUILDING	UNIVERSITY PARK	PA	16802	CENTRE	USA	Blood Diseases and Resources Research	000	7	6/15/1998	NON-COMPETING CONTINUATION	$152,702
														Subtotal = $152,702

Grand Total All Awards = $5,131,899

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EPO regulated erythropoiesis

Award Number: R01HL044491

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/25/2017

PERIOD OF PERFORMANCE END DATE: 02/28/2023

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