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

> **NIH NIH R35** · UNIVERSITY OF IOWA · 2022 · $758,840

## Abstract

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 leu...

## Key facts

- **NIH application ID:** 10375485
- **Project number:** 5R35HL139926-05
- **Recipient organization:** UNIVERSITY OF IOWA
- **Principal Investigator:** Anil Kumar Chauhan
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $758,840
- **Award type:** 5
- **Project period:** 2018-04-01 → 2025-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10375485

## Citation

> US National Institutes of Health, RePORTER application 10375485, Targeting Pyruvate Kinase M2: A novel strategy to combat thrombo-inflammation (5R35HL139926-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10375485. Licensed CC0.

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