# Mechanistic and functional dissection of inflammaging in Down syndrome

> **NIH NIH R01** · BENAROYA RESEARCH INST AT VIRGINIA MASON · 2022 · $677,851

## Abstract

Project Summary/Abstract
 The immune system becomes functionally impaired with aging (inflammaging), impacting risk and
outcome of infection, vaccination, cancer, cardiovascular disease and autoimmunity. Individuals with Down
syndrome (DS) exhibit clinical, cellular and biochemical features of inflammaging, including increased
autoimmunity, decreased naïve T cells and increased pro-inflammatory cytokines. We developed a novel
unbiased approach to analyze immune architecture in people with DS and quantitatively showed that people
with DS exhibit advanced immune aging beginning in childhood driven in part by dysregulation of naïve CD4+ T
cells. This approach showed shared features of advanced immune aging in DS and other autoimmune
disease, suggesting functional relevance and overlap. Therefore, understanding (i) how advanced immune
aging explains impaired functional immune responses in DS, and (ii) how dysregulation of naïve CD4+ T cells
contributes to advanced immune aging, will help us develop novel therapeutic strategies to address immune
defects in DS. Moreover, this understanding will help us identify subsets of the general population who may
benefit from similar therapeutic strategies. This also establishes a basis to understand which genes on
chromosome 21 drive advanced immune aging, with attendant mechanistic and translational implications. We
hypothesize that advanced immune aging impairs immune responses by dysregulating naïve CD4+ T
cells via cell-intrinsic and cell-extrinsic pathways. We propose key experiments here to advance our
understanding of immune aging and immune response in DS. Our specific aims are:
1: Dissecting mechanistic features of naïve CD4+ T cell dysregulation in DS-inflammaging. We will
leverage a novel DS biorepository that I helped establish at BRI to examine how DS impacts CD4+ T cell
biology in the absence of confounding immune disorders. We will use in vitro assays coupled with RNAseq to
identify and test candidate mechanisms. We will study individuals with mosaic DS to provide unique insight to
dissect the cell-intrinsic roles of trisomy 21 in CD4+ T cell dysregulation in vivo.
2: Interrogate phenotypic and functional features of DS-inflammaging in vivo. We will use our immune
cellular clock to quantitatively understand how inflammaging impacts vaccine response in people with DS and
controls. We will also examine robustness of our DS-inflammaging findings in an independent cohort and
follow our original cohort longitudinally to evaluate temporal progression of DS-inflammaging.

## Key facts

- **NIH application ID:** 10520949
- **Project number:** 1R01AI166835-01A1
- **Recipient organization:** BENAROYA RESEARCH INST AT VIRGINIA MASON
- **Principal Investigator:** Bernard Khor
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $677,851
- **Award type:** 1
- **Project period:** 2022-09-01 → 2027-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10520949

## Citation

> US National Institutes of Health, RePORTER application 10520949, Mechanistic and functional dissection of inflammaging in Down syndrome (1R01AI166835-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10520949. Licensed CC0.

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