# Partnerships for Biomedical Research in Arkansas

> **NIH NIH P20** · UNIV OF ARKANSAS FOR MED SCIS · 2023 · $606,274

## Abstract

ABSTRACT
In the last 2 decades, the all-age death rate from chronic kidney disease (CKD) has nearly doubled, and its all-
age prevalence increased by 30% to 700 million people world-wide. Most of these deaths are related to
cardiovascular diseases, including thrombotic cardiovascular events. Cardiovascular risk increases as the
severity of CKD increases (i.e., declining glomerular filtration rate [GFR]). Potential mechanisms underlying this
high cardiovascular risk include increased inflammation and platelet activation. Coinciding with this increased
cardiovascular risk is heightened inflammation, one of the hallmarks of the CKD state. The simplest model to
account for thrombosis and inflammation in the CKD patient is one in which platelets drive inflammation and
thrombosis. Platelet microparticles are small vesicles released during platelet activation and play a significant
role in driving inflammation. We have observed platelet P2Y12 receptor-dependent inflammation in patients
with CKD that was modifiable with a P2Y12 antagonist. Specifically, we found that ticagrelor, a potent platelet
P2Y12 antagonist, decreased inflammation in CKD patients. Because our pilot clinical study did not
demonstrate mechanisms for how platelets modulate leukocyte phenotype in CKD patients, we now propose a
mechanistic study to investigate if P2Y12 antagonism alters release of platelet microparticles that could
potentially explain its anti-inflammatory response in non-dialysis CKD patients. We will recruit 50 non-dialysis
CKD patients with GFR <45 (±P2Y12 antagonist) and 25 matched controls with normal kidney function (total
N=75) to compare release of platelet microparticles. We hypothesize that P2Y12 receptor antagonism will alter
release of platelet microparticles in CKD patients. We will also use bulk RNA sequencing of leukocytes and
proteomics of platelet microparticles to determine if P2Y12 antagonism alters protein expression of platelet
microparticles or leukocyte gene expression in CKD patients to resemble that of controls with normal kidney
function. We hypothesize that P2Y12 receptor antagonism with ticagrelor will inhibit platelets and alter protein
expression of platelet microparticles, resulting in favorable reprogramming of leukocyte gene expression.
Finally, preclinical studies in mouse models will examine the direct effects of platelets deficient in releasing
platelet microparticles (± CKD) on normal leukocyte function. If P2Y12 antagonism reduces the inflammatory
burden of CKD by altering release of platelet microparticles that results in reprogramming of leukocytes, it will
lay the groundwork for studying the anti-inflammatory effect of P2Y12 antagonism on CV events in this high-
risk patient population. Likewise, platelet microparticle proteome and leukocyte transcriptome data will inform
future mechanistic studies to understand CKD pathophysiology. Defining these mechanisms would establish
new therapeutic targets with the potential to reduce bot...

## Key facts

- **NIH application ID:** 10852604
- **Project number:** 3P20GM103429-22S2
- **Recipient organization:** UNIV OF ARKANSAS FOR MED SCIS
- **Principal Investigator:** Lawrence E Cornett
- **Activity code:** P20 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $606,274
- **Award type:** 3
- **Project period:** 2001-09-30 → 2025-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10852604

## Citation

> US National Institutes of Health, RePORTER application 10852604, Partnerships for Biomedical Research in Arkansas (3P20GM103429-22S2). Retrieved via AI Analytics 2026-06-10 from https://api.ai-analytics.org/grant/nih/10852604. Licensed CC0.

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