The role of eosinophil in thrombosis and atherosclerosis in LNK deficiency

Active Project Grant Awarded Last action

Award ID
R01HL168392
Recipient
Awarding agency
Obligated
$5,441,064

Award facts

Assistance listing
93.837 Cardiovascular Diseases Research
Completion date 70% complete
Place of performance
New York, NY 10032, USA

Award details come from USAspending.gov.

Description

As the agency reported it.

Abstract
Atherothrombotic cardiovascular disease (ACD) remains the major cause of morbidity and mortality in the US. Increased number and activation of neutrophils and eosinophils are associated with increased risk of ACD. The underlying mechanisms of these associations are incompletely understood, and no therapies specifically address these risk factors. Human gwas have unraveled association of a common polymorphism of LNK/SH2B3 (t allele, R262W) with an increased risk of ACD and increased neutrophil, platelet and eosinophil counts. This LNK variant is carried by ~75% european, ~50% latin american and ~30% african american populations. We have shown that LNK(R262W) reduces LNK function and LNK deficiency in blood cells promotes atherosclerosis in mouse models. More recently, we have shown that enhanced neutrophil extracellular trap formation promotes atherothrombosis in LNK-/- mice. Mechanistically, activated LNK deficient platelets present increased oxidized phospholipids, priming neutrophils for netosis. While eosinophils represent a small fraction of white blood cells, there is accumulating evidence that they play an important role in thrombosis and atherosclerosis. We have preliminary data showing prominent eosinophilia and reversal of accelerated thrombosis in LNK-/- mice by antibody mediated eosinophil depletion. The preliminary data suggests a major role of eosinophils in eosinophil, neutrophil and platelet interactions that promotes thrombosis in hematopoietic LNK-/- mice. The broad goal of this project is to investigate mechanisms connecting LNK deficiency to atherosclerosis and thrombosis. A major new hypothesis is that hematopoietic LNK deficiency promotes arterial thrombosis, plaque erosion and atherosclerosis at least in part via increased eosinophil production, eosinophil activation and interaction with platelets and neutrophils. In this proposal, we will follow the leads and generate novel mouse models including a mouse line with floxed LNK to explore the mechanisms underlying the role of eosinophils in atherosclerosis and atherothrombosis in hematopoietic LNK deficiency. A better understanding of these mechanisms may lead to development of new therapeutic approaches to managing ACD risks, probably in populations with defined genetic background, e.g. LNK(R262W) polymorphism.

Transactions

Action Obligated Date
Amendment $18,397
Amendment $582,603
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Amendment $62,530
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Amendment $62,530
Amendment $562,766
Amendment $562,766
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Amendment $62,715
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Amendment $564,459
Amendment $564,459
Original award $564,459
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Subawards

Subrecipient Amount Awarded
Mayo Clinic Arizona Dr. Jacobsen is providing expertise in eosinophil biology. Having worked with eosinophils in mice and humans for more than 17 years and will advise and guide… $13,632
Mayo Clinic Arizona lizabeth A. Jacobsen, PhD, Co-Investigator (0.6 person months each year) . Dr. Jacobsen is providing expertise in eosinophil biology. Having worked with… $13,632
Cardiff University Dr. O’Donnell’s laboratory conducts research into the roles of oxidized phospholipids and oxylipins in health and disease. She has the capacity to conduct the… $10,800
Cardiff University Subcontract Scope of Work Dr. O’Donnell’s laboratory conducts research into the roles of oxidized phospholipids and oxylipins in health and… $8,395
Mayo Clinic Arizona Elizabeth A. Jacobsen, PhD, Co-Investigator (0.6 person months each year) . Dr. Jacobsen is providing expertise in eosinophil biology. Having worked with… $13,632
Mayo Clinic Arizona $13,632

Quick answers

Who received award R01HL168392?

R01HL168392 was awarded to The Trustees Of Columbia University In The City Of New York by National Heart Lung and Blood Institute (National Institutes of Health) on January 1, 2024.

How much is award R01HL168392 worth?

$5,441,064 has been obligated on R01HL168392.

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