# A Novel Approach to Molecular Cell Pathologies of Human Down Syndrome and DS-AD

> **NIH NIH R01** · UNIV OF MASSACHUSETTS MED SCH WORCESTER · 2020 · $409,460

## Abstract

ABSTRACT
Down Syndrome (DS), or Trisomy 21, is the leading genetic cause of developmental and cognitive disability in
children. As individuals with DS live longer, we now realize most develop early-onset Alzheimer Disease (AD).
In addition, people with DS have greatly increased risk of congenital heart disease, myeloproliferative disorder
and leukemia, as well as immune and other system defects. Hence, understanding how three copies of normal
genes on chromosome 21 impacts cell expression profiles and cell phenotypes is important not only for DS,
but for conditions that afflict the non-DS population, particularly AD, perhaps the biggest medical challenge of
our time. Researchers have sought to identify the transcriptional and phenotypic changes responsible for the
various aspects of DS; however, this work is hampered by individual variation as well as the genetic complexity
and phenotypic variability of DS. Thus, there is a critical need for better ways to determine specific cellular
pathologies and gene pathways which underlie aspects of the syndrome, and to facilitate screening of drugs to
correct them. We have recently created and demonstrated such a system and, supported by compelling
preliminary results, propose to use it to “dissect” the cellular impact of Trisomy 21, on genome-wide pathways
and phenotypes, in undifferentiated pluripotent and in neural DS stem cells. We will capitalize upon this unique
system to investigate the most direct effects of Trisomy 21 on genome-wide changes in expression of specific
genes and pathways (Aim1), correlate this with specific neural cell phenotypic changes (Aim2), and ultimately
examine the contribution of specific Chr21 genes (Aim 3) to DS and AD pathology. Rather than focus on one or
more “favored” aspects or hypotheses, we propose an unbiased and broad approach, supported by several
collaborators who are leaders in their areas of molecular cell biology and neurobiology. This novel approach
has great promise to surmount challenges that have confounded clear understanding of the basic biology of
DS, and thus provide the foundation for longer-term translational efforts to treat DS. Greater understanding of
genes and cell pathways perturbed in human DS is important for development of drug therapies (for DS and
AD), but also has implications for the potential development of “chromosome silencing” or gene therapies.
This work also has broad basic impact for understanding genome balance, the coordinated levels of
expression for genes throughout the genome.

## Key facts

- **NIH application ID:** 9939595
- **Project number:** 5R01HD091357-04
- **Recipient organization:** UNIV OF MASSACHUSETTS MED SCH WORCESTER
- **Principal Investigator:** JEANNE Bentley LAWRENCE
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $409,460
- **Award type:** 5
- **Project period:** 2017-09-12 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9939595

## Citation

> US National Institutes of Health, RePORTER application 9939595, A Novel Approach to Molecular Cell Pathologies of Human Down Syndrome and DS-AD (5R01HD091357-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9939595. Licensed CC0.

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