# Dissecting T and B cell dysregulation in people with Down syndrome

> **NIH NIH R01** · BENAROYA RESEARCH INST AT VIRGINIA MASON · 2024 · $453,873

## Abstract

PROJECT SUMMARY/ABSTRACT
This is a request for an Administrative Supplement for the INCLUDE Project for R01 AI166835 “Mechanistic
and functional dissection of inflammaging in Down syndrome” in accordance with NOT-OD-22-137. The
overarching goal of the parent grant is to advance our understanding of immune aging and immune response
in DS. The proposed studies for the Administrative Supplement are within the scope of the active parent grant,
focused on Down syndrome (DS) and address INCLUDE Project priorities Component 1 (Targeted high risk –
high reward basic science studies highly relevant to DS) and Component 2 (Assembly of a large cohort of
individuals with DS across the lifespan to perform deep phenotyping and study co-existing conditions). Our
central hypothesis is that the immune features linked to impaired function in people with DS represent a subset
of globally dysregulated features and are driven by cell-intrinsic and/or cell-extrinsic mechanisms. This
hypothesis is based on the following: 1) Studies in vaccine response and in autoimmunity showing that the
phenotype of antigen-specific cells is a subset of memory cell phenotypes, and 2) our data showing that
immune features dysregulated in people with DS can be dysregulated by either cell-intrinsic mechanisms (e.g.
DYRK1A) or cell-extrinsic mechanisms (e.g. IL-6). We expect our proposed studies in people with DS to better
define vaccine-specific cells and the mechanisms underlying their dysregulation, thus providing key scientific
foundation to improve vaccine response and, more broadly, immune function in this group. Our objectives for
the Administrative Supplement are: 1) Enhance our existing DS biorepository by improving phenotypic data
collection and curation and including more individuals with mosaic DS (Component 2), 2) Use phenomics to
broadly identify CD4 T cell features dysregulated by cell-intrinsic vs cell-extrinsic mechanisms in people with
DS (Component 1), and 3) Define dysregulation of vaccine-specific B cells in people with DS (Component 1).
The proposed work leverages our group's published success in developing a cohort of individuals with DS and
in building new tools to interrogate immune landscape and antigen-specific cell phenotype. It leverages many
resources from the parent grant including cohorts (Aim 1a and 3), samples (Aim 3), postdoc effort (Aim 2 & 3),
and computational analysis effort (Aim 2 and 3A). The proposed studies take advantage of interim
experimental advances we have made to synergistically extend parent grant studies, thus promising
synergistic return on investment (Aims 2 and 3). This is particularly important considering the limited nature of
participants and samples. Importantly, we have built in plans to share tools and information from the proposed
studies via the INCLUDE Data Hub. Thus, all the proposed studies are directly responsive to the RFA and are
likely to significantly advance our understanding of immune dysregulation in people with DS ...

## Key facts

- **NIH application ID:** 11167301
- **Project number:** 3R01AI166835-03S1
- **Recipient organization:** BENAROYA RESEARCH INST AT VIRGINIA MASON
- **Principal Investigator:** Bernard Khor
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $453,873
- **Award type:** 3
- **Project period:** 2022-09-01 → 2027-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11167301

## Citation

> US National Institutes of Health, RePORTER application 11167301, Dissecting T and B cell dysregulation in people with Down syndrome (3R01AI166835-03S1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/11167301. Licensed CC0.

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