# Type I Interferon Dysregulation in Down Syndrome

> **NIH NIH R01** · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · 2021 · $320,158

## Abstract

Project Summary
 Type I interferons (IFN-Is) are potent cytokines, playing a key role in the antiviral response. However,
they can also be detrimental to human health. Type I interferonpathies are disorders known to be caused by
IFN-I dysregulation. Mendelian type I interferonopathies, such as Aicardi–Goutières syndrome (AGS), illustrate
how the dysregulation of IFN activity can lead to neurological and autoimmune diseases.
 Down syndrome (DS) is the most common genetic cause of intellectual and developmental disabilities in
children and young adults, affecting over 200,000 individuals in the US. In addition to cognitive problems,
individuals with DS often have cardiac and gastrointestinal abnormalities. They also have various immunity-
related defects, ranging from increased susceptibility to an array of infectious diseases to autoimmunity.
Unfortunately, the exact molecular mechanism underlying these immune defects has yet to be elucidated.
 In most cases, DS is caused by the presence of an extra chromosome 21. Interestingly, the 200 or so
genes present on this autosome include those encoding the type I interferon receptors (IFNAR1 and IFNAR2),
suggesting a possible effect of gene dosage. Given that some type I interferonopathies are driven by minute
increases in the levels of IFN-I cytokines, we decided to investigate the regulation of IFN-I in individuals with
DS. This proposal is built around the hypothesis that the relative levels of IFNAR1 and IFNAR2 are the
essential factors controlling the responsiveness to and duration of IFN-I responses in a cell type-specific
manner in individuals with DS, thereby contributing to the disease. We plan to test this hypothesis, by studying
DS patients in vitro, ex vivo, and in vivo at the molecular, immunological, neurological and clinical levels, to
assess the functional effects of the increases in the dosage of these genes on the regulation of the IFN
pathway in humans.
 A deeper understanding of the molecular regulation of IFN-I in DS will provide us with greater insight into
the pathophysiology of DS and pave the way for the possible use of inhibitors to alleviate the persistent
inflammatory disorders associated with DS.

## Key facts

- **NIH application ID:** 10474048
- **Project number:** 3R01AI150300-01S2
- **Recipient organization:** ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
- **Principal Investigator:** Dusan Bogunovic
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $320,158
- **Award type:** 3
- **Project period:** 2019-09-16 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10474048

## Citation

> US National Institutes of Health, RePORTER application 10474048, Type I Interferon Dysregulation in Down Syndrome (3R01AI150300-01S2). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10474048. Licensed CC0.

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