# Role of POT1 mutations in glioma initiation

> **NIH NIH K08** · BAYLOR COLLEGE OF MEDICINE · 2021 · $176,414

## Abstract

PROJECT SUMMARY
Diffuse gliomas comprise the majority of malignant primary brain tumors and are commonly fatal. In a quest to
better understand their biology, many glioma-associated mutations have been identified over the past decade.
Among these, we have shown that germline mutations in POT1 are associated with increased risk of glioma
development. POT1 is known to bind and protect telomeres, and several POT1 mutations in other cancers are
known to result in telomere elongation. However, it is not known whether the glioma-associated POT1
mutations can cause telomere elongation, and more fundamentally, the mechanisms linking germline POT1
mutations to glioma initiation are not understood. The overall goal of this proposal is to determine how POT1
mutations facilitate glioma initiation. I hypothesize that POT1 mutations accomplish this by (1) driving cell
proliferation and (2) enabling telomere elongation and bypass of replicative senescence. We plan to use glial
progenitor cells (GPCs) as a model for glioma initiating cells. We will use mouse GPCs to address the first
hypothesis, as mice allow in vivo modeling, and human GPCs to address the second hypothesis, as human
cells are more readily capable of replicative senescence. My first Specific Aim seeks to quantify the effects of
POT1 mutant expression or loss of mouse POT1 orthologs in GPC proliferation and fate in vivo, using an in
utero electroporation mouse model, as well as in vitro, at various time points into adulthood. We will also
assess these effects in lineage-restricted GPCs using selective promoters to drive gene expression. My
second Specific Aim seeks to establish the role of POT1 mutations in replicative senescence bypass using
human GPCs. We will assess the effects of POT1 mutant expression or POT1 loss on telomere length and
population doubling capacity of human GPCs. We will also quantify the tumorigenesis potential of these cells in
a xenograft model upon inhibition of p53 and activation of Ras pathways. These studies will help to reveal the
role of POT1 mutations in glioma initiation. In the long term, I intend to leverage this knowledge to gain further
insight into the mechanisms of telomere biology in glioma and translate its vulnerabilities into potential
therapeutic measures. I envision a career for myself as an independent physician-scientist studying the biology
and genetics of gliomas with an active brain tumor surgical practice focused on treating patients with glioma.
To reach this goal, I have identified several areas of deficiency in my training that require addressing. These
include knowledge of telomere biology and genetic engineering techniques as well as bench and laboratory
management skills. I plan to address these deficiencies by learning from my mentor and colleagues as well as
participation in courses and conferences. Baylor College of Medicine and Department of Neurosurgery provide
a highly fertile environment for research, and I enjoy the full support of ...

## Key facts

- **NIH application ID:** 10240676
- **Project number:** 5K08NS110976-03
- **Recipient organization:** BAYLOR COLLEGE OF MEDICINE
- **Principal Investigator:** Ali Jalali
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $176,414
- **Award type:** 5
- **Project period:** 2019-09-30 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10240676

## Citation

> US National Institutes of Health, RePORTER application 10240676, Role of POT1 mutations in glioma initiation (5K08NS110976-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10240676. Licensed CC0.

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