Tuesday, July 1, 2025 7/1/2025

Targeting Pyruvate Kinase M2: A novel strategy to combat thrombo-inflammation

Award Number: R35HL139926
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/01/2018
PERIOD OF PERFORMANCE END DATE: 03/31/2025

Group Awards By:

View Award Description

Targeting Pyruvate Kinase M2: A novel strategy to combat thrombo-inflammation - Project summary Cardiovascular disease (CVD) and stroke claim more lives than all forms of cancer combined and result in an immense health and economic burden (>$316 billion annually in the United States). Current strategies to prevent acute coronary syndromes and ischemic stroke in at risk patients rely on anti-platelet drugs (e.g. aspirin and P2Y12 inhibitors), which do not translate into clinical efficacy in 1/3rd of patients. More potent anti- platelet agents such as Glycoprotein IIbIIIa inhibitors (e.g. abciximab) are associated with bleeding complications and are not suitable for long-term use. Since CVD and stroke are characterized by thrombosis and inflammation, an ideal drug would be one that inhibits thrombo-inflammatory responses without major bleeding and activates inflammation resolution programs leading to polarization of macrophages from an M1 (pro-inflammatory) to an M2 (anti-inflammatory) phenotype. To accomplish this, we are exploring an innovative strategy to inhibit thrombo-inflammation by manipulating aerobic glycolysis in activated platelets and leukocytes. Our approach will be to target the key regulatory enzyme of aerobic glycolysis, pyruvate kinase M2 (PKM2). This approach takes advantage of the recent discovery that, like most normal cells, resting platelets and leukocytes rely primarily on oxidative phosphorylation to generate ATP, whereas activated platelets and leukocytes exhibit a high level of aerobic glycolysis (conversion of glucose to lactate in the presence of oxygen). Notably, recent evidence indicates that PKM2 is highly expressed in the monocytes and macrophages from patients with coronary artery disease, and a driver of M1 macrophage polarization. Utilizing novel mutant platelet-specific PKM2 deficient and myeloid-specific PKM2 deficient strains, we have generated preliminary data that suggests a role for PKM2 in modulating thrombo-inflammation. The goals of this research program are to further understand how PKM2 regulates platelet and leukocyte function and to determine if targeting dimeric PKM2 will inhibit thrombo-inflammation in a murine model of hyperlipidemia. To promote the success of this innovative and high reward program, we will utilize complementary genetic and pharmacological approaches and state-of-the art intravital microscopy, and follow updated Stroke Therapy Academic Industry Roundtable (STAIR) pre-clinical guidelines. We have all the tools, including reagents and state-of-the art intravital microscopy and animal models, to accomplish our goals. I have the prerequisite experience as evidenced by my track record, which has shown high productivity and an upward trajectory in the field of thrombo-inflammation. I have assembled a group of basic scientists and clinicians whose expertise will help guide the proposed research from bench to clinic. This project has significant clinical implications since a clear understanding of energy metabolism and its functional consequences on platelet and leukocyte function could identify novel therapeutic targets common to both thrombosis and inflammation, which may improve outcomes in patients at high risk for thrombo-inflammatory disorders including acute ischemic stroke.


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: 2025 ( Subtotal = $0 )
2025	2024	THE UNIVERSITY OF IOWA	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Blood Diseases and Resources Research	001	7	6/16/2025	NON-COMPETING CONTINUATION	$0
2025	2024	THE UNIVERSITY OF IOWA	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Blood Diseases and Resources Research	000	7	3/25/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $743,663 )
2024	2024	THE UNIVERSITY OF IOWA	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Blood Diseases and Resources Research	001	7	6/21/2024	NON-COMPETING CONTINUATION	$60,706
2024	2024	THE UNIVERSITY OF IOWA	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Blood Diseases and Resources Research	000	7	3/21/2024	NON-COMPETING CONTINUATION	$682,957
														Subtotal = $743,663

Issue Date FY: 2023 ( Subtotal = $758,840 )
2023	2023	THE UNIVERSITY OF IOWA	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Blood Diseases and Resources Research	000	6	2/21/2023	NON-COMPETING CONTINUATION	$758,840
														Subtotal = $758,840

Issue Date FY: 2022 ( Subtotal = $758,840 )
2022	2022	UNIVERSITY OF IOWA, THE	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Blood Diseases and Resources Research	001	5	6/15/2022	NON-COMPETING CONTINUATION	$75,886
2022	2022	UNIVERSITY OF IOWA, THE	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Blood Diseases and Resources Research	000	5	4/2/2022	NON-COMPETING CONTINUATION	$682,954
														Subtotal = $758,840

Issue Date FY: 2021 ( Subtotal = $758,840 )
2021	2021	UNIVERSITY OF IOWA, THE	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Blood Diseases and Resources Research	000	4	3/19/2021	NON-COMPETING CONTINUATION	$758,840
														Subtotal = $758,840

Issue Date FY: 2020 ( Subtotal = $758,840 )
2020	2020	UNIVERSITY OF IOWA, THE	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Blood Diseases and Resources Research	001	3	3/3/2020	NON-COMPETING CONTINUATION	$758,840
2020	2019	UNIVERSITY OF IOWA, THE	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Blood Diseases and Resources Research	000	2	2/12/2020	NON-COMPETING CONTINUATION	$0
														Subtotal = $758,840

Issue Date FY: 2019 ( Subtotal = $758,840 )
2019	2019	UNIVERSITY OF IOWA, THE	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Blood Diseases and Resources Research	000	2	4/1/2019	NON-COMPETING CONTINUATION	$758,840
														Subtotal = $758,840

Issue Date FY: 2018 ( Subtotal = $758,840 )
2018	2018	UNIVERSITY OF IOWA, THE	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Blood Diseases and Resources Research	000	1	2/21/2018	NEW	$758,840
														Subtotal = $758,840

Grand Total All Awards = $5,296,703

Top

All Categories

About

Search

Reports

Data Submission

Award Information

Targeting Pyruvate Kinase M2: A novel strategy to combat thrombo-inflammation

Award Number: R35HL139926

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 04/01/2018

PERIOD OF PERFORMANCE END DATE: 03/31/2025

Federal Websites

Department of Health & Human Services

HHS Operating Divisions

HHS Staff Divisions

Download A Document Viewer