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Principal Investigator: Anil Kumar Chauhan
Organization: UNIVERSITY OF IOWA
Fiscal Year: 2024
Award: $743,663
Funding agency: National Heart Lung and Blood Institute
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.
Terms: <Acetylsalicylic Acid><Acute><Animal Model><Animal Models and Related Studies><Anti-Inflammatories><Anti-Inflammatory Agents><Anti-inflammatory><Antiplatelet Agents><Antiplatelet Drugs><Apoplexy><Aspirin><Biologic Models><Biological Models><Bleeding><Blood Platelets><Blood leukocyte><Blood monocyte><Brain Vascular Accident><Cancers><Cardiovascular Diseases><Cerebral Stroke><Cerebrovascular Apoplexy><Cerebrovascular Stroke><Clinical><Coronary Arteriosclerosis><Coronary Artery Disease><Coronary Artery Disorder><Coronary Atherosclerosis><D-Glucose><Data><Dextrose><Disease><Disorder><Drugs><Economic Burden><Economics><Energy Expenditure><Energy Metabolism><Enzyme Gene><Enzymes><Exhibits><Genetic><Glucose><Glycoproteins><Goals><Guidelines><Health><Hemorrhage><Hyperlipemia><Hyperlipidemia><Industry><Inflammation><Inflammatory><Ischemic Stroke><Leukocytes><Leukocytes Reticuloendothelial System><Macrophage><Malignant Neoplasms><Malignant Tumor><Marrow leukocyte><Marrow monocyte><Marrow platelet><Medication><Mice><Mice Mammals><Model System><Murine><Mus><Myelogenous><Myeloid><Mφ><Normal Cell><O element><O2 element><Oxidative Phosphorylation><Oxidative Phosphorylation Pathway><Oxygen><Patients><Pharmaceutical Preparations><Phenotype><Platelets><Productivity><Pyruvate Kinase><Reagent><ReoPro><Research><Resolution><Rest><Risk><Role><Scientist><Stroke><Testing><Thrombocytes><Thrombosis><United States><Update><White Blood Cells><White Cell><abciximab><acute coronary syndrome><aerobic glycolysis><atherosclerotic coronary disease><bench bed side><bench bedside><bench to bed side><bench to bedside><bench to clinic><bench to clinical practice><blood loss><brain attack><c7E3 Fab><cardiovascular disorder><cerebral vascular accident><cerebrovascular accident><clinical efficacy><combat><coronary arterial disease><dimer><drug/agent><economic><experience><high reward><high risk><improved><improved outcome><inhibitor><innovate><innovation><innovative><intra-vital microscopy><intravital microscopy><malignancy><model of animal><monocyte><mouse model><murine model><mutant><neoplasm/cancer><new approaches><new drug target><new druggable target><new pharmacotherapy target><new therapeutic target><new therapy target><novel><novel approaches><novel drug target><novel druggable target><novel pharmacotherapy target><novel strategies><novel strategy><novel therapeutic target><novel therapy target><pharmacologic><phosphoenol transphosphorylase><phosphoenolpyruvate kinase><pre-clinical><preclinical><prevent><preventing><programs><resolutions><response><social role><stroke model><stroke outcome><stroke therapy><stroke treatment><stroked><strokes><success><therapeutic target><thromboinflammation><thromboinflammatory><thrombotic disease><thrombotic disorder><tool><treating stroke><white blood cell><white blood corpuscle>