# Regulation and manipulation of the telomerase RNA component in hematopoiesis

> **NIH NIH R01** · BOSTON CHILDREN'S HOSPITAL · 2022 · $479,272

## 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, cardiovascular disease, pulmonary
fibrosis, and cirrhosis. Recent work identifies the non-canonical polymerase PAPD5 as a key negative regulator
of TERC. PAPD5 is thus a novel target for small molecule inhibitors to restore TERC and telomeres in human
diseases. What is not known is the basis of selective regulation of non-coding RNAs (ncRNAs) by PAPD5, nor
whether inhibiting PAPD5 will be therapeutically effective. The overall objectives of this proposal are (1) to
understand how PAPD5 selectively regulates ncRNAs, and (2) to determine the in vivo efficacy of PAPD5
inhibitors in restoring hematopoietic stem cell (HSC) function. The central hypothesis is that PAPD5
selectively regulates TERC and a small number of ncRNAs, providing a therapeutic window for systemic
PAPD5 inhibition to restore telomeres and self-renewal capacity in stem cells. The rationale for our work
is that understanding mechanisms of selectivity and demonstrating therapeutic efficacy of small molecule PAPD5
inhibitors will provide a strong scientific framework for their development as treatments for bone marrow failure
and a range of diseases. The central hypothesis will be tested by pursuing two Specific Aims: (1) Identify the
mechanisms of selective regulation of ncRNAs by PAPD5, and (2) Determine the therapeutic efficacy of
PAPD5 inhibitors in vivo. Under the first aim, biochemical and genetic approaches will be used to rigorously
identify bona fide PAPD5 targets, and to decipher the regulatory logic of the PAPD5-dependent transcriptome in
human cells, emphasizing HSCs. Tools and techniques that have been developed and demonstrated to be
feasible in the applicants’ hands will be used. Under the second aim, the therapeutic efficacy of small molecule
PAPD5 inhibitors to restore telomere maintenance and HSC function in vivo will be determined. New approaches
to overcome interspecies differences in telomere biology and model human HSC failure will be applied. The
approach is innovative because PAPD5 is a long-sought, novel and tractable target regulating TERC, the
inhibition of which may enable a systemic telomerase-modulating therapy that selectively impacts stem cells.
The proposed research is significant, because it is expected to yield ...

## Key facts

- **NIH application ID:** 10426334
- **Project number:** 5R01DK107716-07
- **Recipient organization:** BOSTON CHILDREN'S HOSPITAL
- **Principal Investigator:** SUNEET AGARWAL
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $479,272
- **Award type:** 5
- **Project period:** 2015-12-01 → 2026-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10426334

## Citation

> US National Institutes of Health, RePORTER application 10426334, Regulation and manipulation of the telomerase RNA component in hematopoiesis (5R01DK107716-07). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10426334. Licensed CC0.

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