# MOLECULAR CONSEQUENCES OF TELOMERASE DYSFUNCTION DURING HEMATOPOIETIC DEVELOPMENT

> **NIH NIH R01** · WASHINGTON UNIVERSITY · 2020 · $381,250

## Abstract

PROJECT SUMMARY/ABSTRACT
 The overarching theme of our research is to decipher the molecular events responsible for bone
marrow failure (BMF) in patients with impaired telomere maintenance, with the goal of improving treatment
outcomes in these patients. The focus of this proposal is to use human pluripotent stem cells (hPSCs) as a
novel platform to understand the molecular regulation of definitive hematopoietic impairment in cells with
disease-associated mutations in telomerase, and to find novel alternatives to increase hematopoietic output in
cells with dysfunctional telomeres.
 Dyskeratosis congenita (DC) is an inherited BMF syndrome where patients have very short telomeres
for their age, typically below the first percentile length when compared to the rest of the population. All
mutations discovered in DC are in genes that affect telomere homeostasis, including mutations in the
telomerase components TERT, TERC, and dyskerin (DKC1). Difficulties in isolating relevant cell populations
from DC patients have precluded the development of therapies against this disease. We recently overcame
this limitation and combined genome engineering in hPSCs with in vitro human hematopoietic differentiation
methods to create a novel and robust platform to study the mechanisms of hematopoietic failure caused by
telomere dysfunction.
 In this submission, three specific aims are proposed that utilize this system to understand the
molecular consequences of telomerase impairment during hematopoietic development, and to decipher novel
targets to rescue hematopoietic output in cells harboring eroded telomeres. In aim 1, we will decipher the role
of DNA damage responses (DDR) in the progression of definitive hematopoietic failure from cells with low
levels of TERC. In particular, we will focus on the role of the p53 pathway in the hematopoietic impairment of
cells with short telomeres, decipher the roles of miR-34a and miR-145 during abnormal hematopoiesis and
decipher the genetic consequences of silencing DDR to restore hematopoietic output in cells harboring DC-
associated mutations. In aim two we will decipher if the modulation of RNA decay in cells harboring mutations
in DKC1 is a viable strategy to restore hematopoietic output in these cells. We will modulate TERC
posttranscriptional processing and degradation by inhibition of specific RNA decay pathways. Finally, in aim 3,
we will investigate if novel, non-canonical roles of TERC outside telomere maintenance can influence
hematopoietic output and potentiate disease phenotypes in patients harboring mutations that reduce TERC
levels, since these are commonly afflicted with severe disease phenotypes.
 Collectively, the studies proposed will allow us to decipher novel targets for directed therapies in
patients suffering with telomere-syndromes. Our unique cellular and molecular tools, combined with our
expertise in telomerase, stem cell biology and hematopoiesis puts us in an ideal position to make a significant
im...

## Key facts

- **NIH application ID:** 9937794
- **Project number:** 5R01HL137793-04
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Luis Francisco Zirnberger Batista
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $381,250
- **Award type:** 5
- **Project period:** 2017-08-01 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9937794

## Citation

> US National Institutes of Health, RePORTER application 9937794, MOLECULAR CONSEQUENCES OF TELOMERASE DYSFUNCTION DURING HEMATOPOIETIC DEVELOPMENT (5R01HL137793-04). Retrieved via AI Analytics 2026-05-29 from https://api.ai-analytics.org/grant/nih/9937794. Licensed CC0.

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