# Regulation of the telomerase RNA component in hematopoiesis

> **NIH NIH R01** · BOSTON CHILDREN'S HOSPITAL · 2020 · $398,250

## Abstract

PROJECT SUMMARY/ABSTRACT. Telomerase is critical for health and longevity, but there is a fundamental
lack of understanding of how it is regulated in human cells. This knowledge gap impedes the ability to develop
therapies for a growing spectrum of disorders in which telomerase dysfunction is implicated. The long-term
goal of this project is to be able to manipulate telomerase in human cells for therapeutic benefit, with a key
target being the hematopoietic system. The level of the noncoding telomerase RNA component TERC is a
critical determinant of telomerase function in cells. Low TERC levels resulting from genetic mutations cause a
wide spectrum of degenerative disorders, including dyskeratosis congenita (DC), aplastic anemia,
MDS/leukemia, solid tumors, pulmonary fibrosis, and cirrhosis. What is not known is how TERC levels are
regulated in cells, which is an important barrier to developing therapeutic strategies to manipulate telomerase.
The overall objective of this proposal is to understand how TERC is regulated in human stem cells including
hematopoietic stem cells (HSCs). The central hypothesis is that cis-acting elements at the TERC locus
and other factors that function post-transcriptionally act in concert to determine the steady-state level
of TERC in cells. The rationale for this work is that deciphering how patient mutations impact TERC
biogenesis will yield a new understanding of how TERC levels are normally regulated, which will in turn reveal
novel approaches to manipulate telomerase activity. The central hypothesis will be tested by pursuing two
Specific Aims: (1) Identify transcriptional mechanisms regulating human TERC expression, and (2)
Identify post-transcriptional mechanisms regulating human TERC levels. Under the first aim, “scarless”
genome-editing in induced pluripotent stem (iPS) cells from DC patients will be used to define the function of
newly identified cis-acting elements in the human TERC locus, and to reveal trans-acting factors that modulate
TERC transcription. Tools and techniques that have been developed and demonstrated to be feasible in the
applicants' hands will be used. Under the second aim, the role of an RNA processing factor recently found to
be disrupted in DC patients who have low TERC levels will be investigated. Using patient iPS cells, which have
been created by the applicant and carry mutations in this gene, the post-transcriptional processing and
maturation of TERC will be investigated. The approach is innovative because the new tools and insights now
available allow a critical shift in focus from the regulation of the catalytic component of telomerase (TERT),
which has been the subject of intense investigation, to the equally important but less well studied RNA
component of telomerase, TERC. The proposed research is significant, because it is expected to yield new
strategies to manipulate telomerase activity in a growing number of hematopoietic and degenerative disorders
including aplastic anem...

## Key facts

- **NIH application ID:** 9844946
- **Project number:** 5R01DK107716-05
- **Recipient organization:** BOSTON CHILDREN'S HOSPITAL
- **Principal Investigator:** SUNEET AGARWAL
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $398,250
- **Award type:** 5
- **Project period:** 2015-12-01 → 2021-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9844946

## Citation

> US National Institutes of Health, RePORTER application 9844946, Regulation of the telomerase RNA component in hematopoiesis (5R01DK107716-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9844946. Licensed CC0.

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