# Mechanisms linking LNK genetic variation to atherothrombosis

> **NIH NIH R01** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2020 · $509,986

## Abstract

Leukocytosis and thrombocytosis are associated with increased atherothrombotic risk in the general
population. LNK is a scaffolding protein that in mice inhibits thrombopoietin signaling in hematopoietic stem
cells (HSCs) and megakaryocyte progenitors. A LNK variant (R262W) has been associated with leukocyte,
platelet counts and CHD in human GWAS. Using human cord blood we discovered an association of the TT
risk SNP (R262W) of LNK with expansion of HSCs, increased TPO signaling and enhanced megakaryopoiesis,
indicating reduced LNK function and increased MPL signaling. To assess the role of reduced LNK function in
atherothrombosis, we transplanted WT or Lnk-/- bone marrow (BM) into irradiated WT or Ldlr-/- mice and fed
recipient mice chow or Western diets (WD), respectively. While the Lnk-/- BM recipients showed similarly
increased platelet counts with both diets, platelet activation, leukocyte counts, formation of platelet/leukocyte
aggregates (PLA), atherosclerosis and thrombosis were markedly increased by hematopoietic Lnk deficiency
combined with hypercholesterolemia. Thus we hypothesize that in the setting of hypercholesterolemia, genetic
variants that cause activation of TPO signaling predispose to atherothrombosis via leukocytosis and platelet
activation. Aim 1 will determine the mechanisms of platelet activation and leukocytosis in mice with
hematopoietic Lnk deficiency and hypercholesterolemia. Aim 2 will assess mechanisms of accelerated
atherosclerosis and thrombosis in these mice and the relative contributions of increased leukocytes, activated
platelets, platelet-leukocyte aggregates and neutrophil-derived NETs to these processes. Therapeutic
interventions with JAK2 or ERK inhibitors or rHDL infusions will be assessed. Aim 3 will employ human cord
blood stem cells in a humanized mouse models to assess the impact of the TT risk SNP on hematopoietic
functions in human cells.

## Key facts

- **NIH application ID:** 9940895
- **Project number:** 5R01HL137663-04
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** ALAN richard TALL
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $509,986
- **Award type:** 5
- **Project period:** 2017-07-01 → 2021-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9940895

## Citation

> US National Institutes of Health, RePORTER application 9940895, Mechanisms linking LNK genetic variation to atherothrombosis (5R01HL137663-04). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/9940895. Licensed CC0.

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