# Tryptophan immune metabolism and vascular inflammation in CKD associated atherosclerosis

> **NIH NIH R56** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2022 · $448,374

## Abstract

PROJECT SUMMARY/ABSTRACT
Cardiovascular disease (CVD) is the leading cause of morbidity and mortality in chronic kidney disease (CKD),
reducing the life expectancy of CKD and dialysis patients to roughly half to one-third that of the general
population. However, the pathogenesis of accelerated CVD in CKD is not yet clearly understood, and no
specific therapeutic strategies are currently available to attenuate this phenomenon. Our long-term goal is to
understand the immune-metabolic mechanisms underlying accelerated atherosclerosis in order to develop
diagnostic and therapeutic solutions to improve the lifespan of patients with CKD. Our overall objective is to
define the role of tryptophan catabolism via the kynurenine pathway (KP) in the pathophysiology of CKD
atherosclerosis. Our central hypothesis is that the tryptophan catabolite kynurenic acid (KA) causes
CKD atherosclerosis, whereas 3-hydroxy anthranilic acid (3-HAA) ameliorates this problem. Our
rationale is that if KP metabolites play a causal role in CKD atherosclerosis, then we can develop new
therapeutic strategies and biomarkers to attenuate the CVD burden in the CKD population. We will test our
central hypothesis by pursuing the following specific aims: 1) demonstrating the role of circulating and
macrophage-specific KA, and 2) delineating the anti-inflammatory role of circulating and macrophage 3-HAA in
the pathogenesis of CKD atherosclerosis. Under Aim 1, we will delineate the effect of circulating KA, define the
role of macrophage KA deficiency using in bio-banked human aortic specimens and CKD atherosclerosis
models, and identify KA-induced macrophage molecular mechanisms like activation of aryl hydrocarbon and
cell-membrane G protein-coupled receptor 35 pathways in the pathogenesis of CKD atherosclerosis.
Regarding Aim 2, we plan to delineate the effect of circulating 3-HAA, define the role of macrophage 3-HAA
using bio-banked aortic samples and CKD atherosclerosis models, and identify the 3-HAA induced
macrophage mechanisms like inflammasome activation in the pathogenesis of CKD atherosclerosis. The
proposed research is innovative in that it links macrophage inflammation and metabolism in CKD and
delineates the contribution of lesional macrophage tryptophan metabolism vs. that of circulating KP metabolites
in CKD atherosclerosis via mass spectrometric metabolic profiling and myeloid-specific KP deficiency in CKD
atherosclerosis models. The proposed research is significant because it will provide strong evidence of the
mechanistic role of tryptophan metabolism in the pathogenesis of CKD atherosclerosis, potentially leading to
the discovery of validated biomarkers and clinical studies to prevent CV events in CKD atherosclerosis.

## Key facts

- **NIH application ID:** 10687399
- **Project number:** 1R56HL159549-01A1
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Anna Vachaparampil Mathew
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $448,374
- **Award type:** 1
- **Project period:** 2022-09-13 → 2023-10-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10687399

## Citation

> US National Institutes of Health, RePORTER application 10687399, Tryptophan immune metabolism and vascular inflammation in CKD associated atherosclerosis (1R56HL159549-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10687399. Licensed CC0.

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