# Netrin-1 in Metabolic and Inflammatory Crosstalk in Cardiometabolic Disease

> **NIH NIH P01** · NEW YORK UNIVERSITY SCHOOL OF MEDICINE · 2022 · $508,500

## Abstract

Summary – Project 2
Cardiovascular disease remains the leading cause of death worldwide, with atherosclerosis being a major
contributor. The unremitting rise in obesity and its co-morbidities, including diabetes and non-alcoholic fatty liver
diseases, further increase the risk of atherosclerosis. While such cardiometabolic diseases were once attributed
primarily to dysregulations of lipid metabolism, it is now appreciated that the immune response to excess lipid in
tissues (artery, adipose tissue, liver) shapes cardiometabolic disease progression and its complications.
Determining the mechanisms underlying this damaging metabolic inflammation, and identifying therapeutic
approaches to quench it, are major focuses of our Program Project Grant (PPG). In its first cycle, our PPG
unveiled key pathways through which alterations in macrophage (Mø) metabolism, trafficking, and tissue-specific
molecular reprogramming drive the chronic inflammation that fuels atherosclerosis, and the metabolic disorders
that accelerate it (e.g., obesity and non-alcoholic steatohepatitis; NASH). Through examination of mouse models
and human tissues from patients with these disorders, Project 2 studies point to pathogenic roles for the
neuroimmune guidance molecule netrin-1 in directing non-resolving inflammation and lipid accumulation in
metabolic tissues. We hypothesize that netrin-1 contributes to dysregulation of Mø metabolism and trafficking,
and molecular re-programming of inflammation, and that these processes are driven by tissue- and environment-
specific stimuli that contribute to cardiometabolic disease. Key Project 2 discoveries in cycle 1 of the PPG
include: (1) Deletion of netrin-1 in myeloid cells protects mice from high fat diet-induced obesity and hepatic
steatosis, and regresses advanced atherosclerosis; (2) Netrin-1 expression alters the functional trajectory of Mø
in obese adipose tissue and atherosclerotic plaques; and (3) Distinct isoforms of netrin-1 accumulate in Mø
during metabolic inflammation that can provoke both receptor-dependent and -independent signaling. In this
proposal, we will investigate how Mø-derived netrin-1 promotes atherosclerosis, obesity and NASH through both
Mø-intrinsic and -extrinsic mechanisms, including cross-talk with other immune cells and parenchymal cells, and
how interventions targeting netrin-1 can be leveraged toward our goal of mitigating cardiometabolic disease.
Together with Projects 1 and 3, we will probe how netrin-1 contributes to intra- and inter-organ communications
through shared tools, strategies and bioinformatics approaches, and test therapeutically relevant approaches to
block its detrimental actions.
Fortified by complementary examinations in human tissues and transcriptome
databases, we will employ state-of-the-art RNA sequencing, coupled with spatial transcriptomics, to generate
and “visualize” a comprehensive map of the putative interactome and upstream transcriptional regulators that
regulate intra- a...

## Key facts

- **NIH application ID:** 10424905
- **Project number:** 2P01HL131481-06
- **Recipient organization:** NEW YORK UNIVERSITY SCHOOL OF MEDICINE
- **Principal Investigator:** KATHRYN J MOORE
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $508,500
- **Award type:** 2
- **Project period:** 2017-05-01 → 2027-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10424905

## Citation

> US National Institutes of Health, RePORTER application 10424905, Netrin-1 in Metabolic and Inflammatory Crosstalk in Cardiometabolic Disease (2P01HL131481-06). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10424905. Licensed CC0.

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