# ASK1 a novel regulator of platelet function

> **NIH NIH R01** · THOMAS JEFFERSON UNIVERSITY · 2020 · $477,012

## Abstract

Cardiovascular disease (CVD) is the number one killer of mankind. Most CVDs are associated
with atherosclerosis and thrombosis. Mounting evidence suggests that platelets are the initiators
of both atherosclerosis and thrombosis. Agonist stimulation in platelets is known to activate
MAPKs, and it has been shown that they are important for platelet activities both in vivo and in
vitro. Despite this evident role of MAPK signaling contributing to platelet functions, the
mechanisms through which they regulate platelet activities are not fully understood. We have
identified that a member of the MAP3K family, apoptosis signal-regulating kinase (ASK1) is
present in both human and murine platelets and is activated by physiological agonists. We have
shown that Ask1 activity supports platelet aggregation and secretion, and ablation of Ask1
confers a protective effect in in vivo models of thrombosis. We therefore hypothesize that
platelet ASK1 is a key regulator of atherogenesis, atherothrombosis, and ischemia
reperfusion (I/R) injury resulting from clot dissolution in MI, and stroke. We have also
identified several structurally distinct ASK1 inhibitors based on information from published virtual
chemical library screens. Two of these compounds have shown excellent efficacy in protecting
mice from thrombosis with minimal effects on hemostasis, as assessed by tail bleeding time and
laser-induced hemostasis model. This R01 proposal is focused on delineating the role of platelet
ASK1 in initiating atherogenesis, atherothrombosis, and aggravating I/R injury. Accordingly,
three Specific Aims have been proposed. Specific Aim 1 will test the hypothesis that platelet
ASK1 is key in initiating atherogenesis. We will use a hyperlipidemia mouse model (Apoe-/- mice
fed with high-fat diet) to study the effect of ablation or inhibition of platelet Ask1 on plaque
formation. Specific Aim 2 will test the hypothesis that platelet ASK1 is a central regulator of
platelet activation during atherosclerotic plaque rupture (atherothrombosis). We will use an
innovative mouse model to mimic thrombus formation at the site of plaque rupture. Specific
Aim 3 will test the hypothesis that platelet ASK1 is responsible for aggravating I/R injury. We
will use the transient middle cerebral artery occlusion model (tMCAO) of stroke to assess the
effect of ablation/inhibition of platelet ASK1 on I/R injury. Successful completion of this proposal
will help to develop a number of therapeutic interventions for thrombosis associated diseases
such as atherosclerosis, MI, and stroke.

## Key facts

- **NIH application ID:** 9899282
- **Project number:** 5R01HL113188-06
- **Recipient organization:** THOMAS JEFFERSON UNIVERSITY
- **Principal Investigator:** ULHAS P NAIK
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $477,012
- **Award type:** 5
- **Project period:** 2019-04-01 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9899282

## Citation

> US National Institutes of Health, RePORTER application 9899282, ASK1 a novel regulator of platelet function (5R01HL113188-06). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/9899282. Licensed CC0.

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