# Down Syndrome as a systemic autophagy deficiency disorder

> **NIH NIH R01** · UNIVERSITY OF COLORADO DENVER · 2020 · $2,594,673

## Abstract

Although enhanced disease risk in the Down Syndrome (DS) population is ultimately caused by trisomy of
chromosome 21 (T21), the likelihood of someone with DS getting any particular disease and the severity of
symptoms are highly variable. In this proposal we will test the hypothesis that deficiencies in macroautophagy
(autophagy) drive differences in critical disease-associated phenotypes in individuals with DS. Autophagy is
the process by which cellular material is recycled via the lysosome, and deficits in autophagy are thought to
contribute to many of the diseases for which people with DS are at enhanced risk. Importantly, it is known that
T21 causes impairment of autophagy; however it has not been addressed whether and how autophagy
impairment contributes to specific manifestations of disease in people with DS. To test our hypothesis, we will
test if variable deficits in autophagy in DS results in enhanced clonal hematopoiesis (CH). CH was chosen for
this study because it is a specific, quantifiable disease phenotype that has major effects on health and which
can be readily monitored in humans and mice from peripheral blood. We recently found that some but not all
children with DS display enhanced CH (as seen in the typical elderly population) that is temporally related to
their >50-fold increase in risk for childhood leukemia. This provides a strong rational for us to test our
hypothesis in human samples and scientifically rigorous mouse models with two aims. Aim 1 will determine the
quantitative relationship between basal autophagic flux and clonal hematopoiesis in DS by leveraging a unique
resource- the Human Trisome Project. This will allow us to perform what we believe will be the largest and
most comprehensive analysis of the relationship between autophagy and any disease state in the Down
Syndrome population. Aim 1 will also determine the molecular mechanisms that underlie the deficit in
autophagy that is caused by T21. In Aim 2, we will test the requirement and sufficiency of autophagy
variation/deficiency to explain enhanced clonal hematopoiesis using state of the art mouse models of DS and
models that allow us to specifically manipulate autophagy. Additionally, we will test if interventions (exercise
and a dietary supplement that has been shown to be safe in people and mice) designed to restore autophagy
can reduce the risk of CH and protect against one of its more serious consequences, i.e. leukemia. Impact:
our work may explain why severity of disease varies widely amongst individuals with DS. More important if it is
feasible to restore autophagy in individuals with DS using relatively benign interventions and thus reduce CH,
this will provide a framework to intervene to reduce risk of disease in people with DS.

## Key facts

- **NIH application ID:** 10108636
- **Project number:** 1R01HD103828-01
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** James V Degregori
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $2,594,673
- **Award type:** 1
- **Project period:** 2020-09-18 → 2024-09-17

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10108636

## Citation

> US National Institutes of Health, RePORTER application 10108636, Down Syndrome as a systemic autophagy deficiency disorder (1R01HD103828-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10108636. Licensed CC0.

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