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Novel regulators of stress erythropoiesis

Award Number: R01DK089439
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: 07/01/2017
PERIOD OF PERFORMANCE END DATE: 05/31/2019

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Novel regulators of stress erythropoiesis - DESCRIPTION (provided by applicant): Anemia as associated with end-stage renal disease, chemo- and radiation therapies, inflammation, myelodysplasia, iron dysregulation and hemoglobinopathies leads to chronic bouts of accelerated, yet stressed and often compromised erythropoiesis. A specific understanding of key regulators of such stress erythropoiesis is of basic importance for insight into new anemia therapies. rhEPO per se can be therapeutic, but has substantial hypertensive side-effects, evokes thrombolytic events, is a high-cost recombinant glycoprotein, and may worsen certain cancers. Via investigations of EPO's effects on primary erythroid progenitors, we have uncovered and initially characterized two important new factors (and associated pathways) that selectively regulate stress erythropoiesis. First, our studies of a novel EPO-induced intracellular Spi2A serpin (via a new KO model) reveal that under select stress conditions, erythroblasts become highly sensitive to lysosome damage to the extent of leaching lysosomal executioner cathepsins- which are inhibited by Spi2A. If unchecked, cathepsin-associated damage and erythroblast death escalate, with ROS and iron as cytotoxic co-factors. We also demonstrate that a Cathepsin B/L inhibitor can phenocopy Spi2A's cytoprotective effects. A second EPO co-induced erythropoietic regulator we have discovered (and are beginning to understand) is the molecular adaptor and pseudokinase, Trib3. By developing a Trib3-KO mouse model, we reveal non-redundant novel stress erythropoiesis specific roles for Trib3 during both early, and late- stage erythroid cell formation We will now advance insight into these two new stress erythropoiesis factors, and coupled pathways, via the following SPECIFIC AIMS: SA#1 will first define how Spi2A and linked pathways impact on stress erythropoiesis due to ß-thalassemia and iron imbalance (#1.1). At a mechanistic level, consequences of Spi2A- deficiency on erythroblast autophagy will be determined and molecular damage incurred by erythroblast lysosomes during oxidative stress plus Spi2A-deficiency will be defined (#1.2). Via LOF studies, SA#2 first will define effects exerted by Trib3 pseudokinase on early- and late-stage erythropoiesis during ß-thalassemia, and iron imbalance (#2.1). Aim 2.2 will determine Trib3's roles in unfolded protein response pathways together with Trib3's regulatory molecular action mechanisms in early- and late- stage erythroid cells. SA#3 will advance studies to primary human erythroid progenitors (including thalassemia), and will first determine effects of lysosomal compromise, and cathepsin inhibition on erythroblast cytoprotection (#3.1). Aim 3.2 will define effects of Trib3 LOF and GOF during erythropoietic stress. Substantial insight will be gained concerning new regulators of red cell formation and novel target pathways within compromised erythroid progenitors for anti- anemia agents.


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: 2019 ( Subtotal = $0 )
2019	2017	UNIVERSITY SYSTEM OF NEW HAMPSHIRE	51 COLLEGE RD SERVICE BLDG 107	DURHAM	NH	03824	STRAFFORD	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	8	9/27/2019	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
														Subtotal = $0

Issue Date FY: 2018 ( Subtotal = $0 )
2018	2017	UNIVERSITY SYSTEM OF NEW HAMPSHIRE	51 COLLEGE RD SERVICE BLDG 107	DURHAM	NH	03824	STRAFFORD	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	8	11/1/2017	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$237,539
2018	2017	MAINE MEDICAL CENTER	22 BRAMHALL ST	PORTLAND	ME	04102	CUMBERLAND	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	7	11/1/2017	NON-COMPETING CONTINUATION	-$33,798
2018	2016	MAINE MEDICAL CENTER	22 BRAMHALL ST	PORTLAND	ME	04102	CUMBERLAND	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	6	11/1/2017	NON-COMPETING CONTINUATION	-$203,741
														Subtotal = $0

Issue Date FY: 2017 ( Subtotal = $337,973 )
2017	2017	UNIVERSITY SYSTEM OF NEW HAMPSHIRE	51 COLLEGE RD SERVICE BLDG 107	DURHAM	NH	03824	STRAFFORD	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	003	8	8/22/2017	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$304,175
2017	2017	MAINE MEDICAL CENTER	22 BRAMHALL ST	PORTLAND	ME	04102	CUMBERLAND	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	7	6/22/2017	NON-COMPETING CONTINUATION	$33,798
2017	2017	MAINE MEDICAL CENTER	22 BRAMHALL ST	PORTLAND	ME	04102	CUMBERLAND	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	7	8/21/2017	NON-COMPETING CONTINUATION	-$304,175
2017	2017	MAINE MEDICAL CENTER	22 BRAMHALL ST	PORTLAND	ME	04102	CUMBERLAND	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	7	4/25/2017	NON-COMPETING CONTINUATION	$304,175
														Subtotal = $337,973

Issue Date FY: 2016 ( Subtotal = $341,247 )
2016	2016	MAINE MEDICAL CENTER	22 BRAMHALL STREET	PORTLAND	ME	04102	CUMBERLAND	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	6	5/11/2016	NON-COMPETING CONTINUATION	$341,247
														Subtotal = $341,247

Issue Date FY: 2015 ( Subtotal = $348,279 )
2015	2015	MAINE MEDICAL CENTER	22 BRAMHALL STREET	PORTLAND	ME	04102	CUMBERLAND	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	5	4/27/2015	NON-COMPETING CONTINUATION	$348,279
														Subtotal = $348,279

Issue Date FY: 2014 ( Subtotal = $360,110 )
2014	2014	MAINE MEDICAL CENTER	22 BRAMHALL STREET	PORTLAND	ME	04102	CUMBERLAND	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	9/9/2014	COMPETING CONTINUATION	$360,110
														Subtotal = $360,110

Issue Date FY: 2012 ( Subtotal = $214,876 )
2012	2012	MAINE MEDICAL CENTER	22 BRAMHALL STREET	PORTLAND	ME	04102	CUMBERLAND	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	7/6/2012	NON-COMPETING CONTINUATION	$214,876
														Subtotal = $214,876

Issue Date FY: 2011 ( Subtotal = $216,983 )
2011	2011	MAINE MEDICAL CENTER	22 BRAMHALL STREET	PORTLAND	ME	04102	CUMBERLAND	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	6/29/2011	NON-COMPETING CONTINUATION	$216,983
														Subtotal = $216,983

Issue Date FY: 2010 ( Subtotal = $225,750 )
2010	2010	MAINE MEDICAL CENTER	22 BRAMHALL STREET	PORTLAND	ME	04102	CUMBERLAND	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	7/26/2010	NEW	$225,750
														Subtotal = $225,750

Grand Total All Awards = $2,045,218

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Novel regulators of stress erythropoiesis

Award Number: R01DK089439

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: 07/01/2017

PERIOD OF PERFORMANCE END DATE: 05/31/2019

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