# Hedgehog/GLI1-mediated regulation of DNA repair in cancer, aging and neurodegenerative diseases

> **NIH NIH R01** · TEXAS TECH UNIVERSITY HEALTH SCIS CENTER · 2022 · $382,500

## Abstract

“Hedgehog/GLI1-mediated regulation of DNA repair in cancer, aging and neurodegenerative diseases”
The overarching goal of this proposal is to identify dysregulated molecular mechanisms that contribute to age-
related neuropathological conditions such as Alzheimer's disease (AD) and malignant diseases, and to develop
novel preventive and treatment strategies. Similar to malignant diseases, DNA damage accumulation and
mitochondrial abnormalities are elevated in aging neurons and AD patients, and may contribute to neuronal
dysfunction, AD pathogenesis and progression. Our laboratory has identified aberrant upregulation of hedgehog
signaling effector molecule and Glioma associate oncogene 1 (GLI1) in ovarian cancer. Its aberrant expression
correlates with cancer stem cell (CSC) phenotype, chemoresistance and disease recurrence. Our preliminary
data presented in the parent grant demonstrated that aberrantly upregulated GLI1 promotes expression of
Fanconi anemia and breast cancer associated (FA-BRCA) DNA repair genes, including BRIP1, BRCA1,
FANCD2 and RAD51 in OC. These aberrantly expressed DNA repair genes can facilitate efficient repair of DNA
double strand breaks (DSB) generated by platinum based chemotherapeutic drugs, and promote acquired
chemoresistance and acquisition of cancer stem cell (CSC) phenotype. Whereas, in the normal tissues GLI1
and FA-BRCA pathway plays important functions in maintaining stem cell pool, important for genomic integrity.
While these DNA repair genes and pathways are mutated or dysregulated in cancers, their deficiency causes
stem cell exhaustion/depletion, early onset of aging, intellectual disabilities and other age related pathologies
including neurodegenerative diseases. However, studies focusing on their regulation in the brain and neuronal
cells during aging and particularly in the context of neurodegenerative diseases is limited. In order to evaluate
the expression of Hh/GLI1 and its dependent expression of FA-BRCA genes in the brains and neuronal cells,
we have collaborated with Dr. Reddy (neuroscientist and leader in this field of aging and AD and ADRD). In this
supplemental proposal, we will particularly study the GLI1 and its dependent regulation of BRCA1 interacting
protein 1 or BRIP1 in the context of aging and during AD pathogenesis. Similar to OC cells and tissues, our
preliminary studies identified expression of GLI1 and BRIP1 in mouse and human brains. Interestingly,
expression analysis indicates diminished levels of BRIP1 transcript and protein levels in aging and AD mouse
brains. BRIP1 is one of the Fe-S cluster, and DEAH domain containing 5’ to 3’ DNA helicases also mutated in
Fanconi anemia (also known as FANCJ) genome instability syndrome with progressive bone marrow failure and
malignant diseases at early in life. BRIP1 functions were reasonably well studied in DNA repair, however, there
is limited data on its role and regulation during aging and neurodegenerative diseases. BRIP1 is highly expres...

## Key facts

- **NIH application ID:** 10498150
- **Project number:** 3R01CA219187-05S1
- **Recipient organization:** TEXAS TECH UNIVERSITY HEALTH SCIS CENTER
- **Principal Investigator:** Komaraiah Palle
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $382,500
- **Award type:** 3
- **Project period:** 2018-02-15 → 2024-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10498150

## Citation

> US National Institutes of Health, RePORTER application 10498150, Hedgehog/GLI1-mediated regulation of DNA repair in cancer, aging and neurodegenerative diseases (3R01CA219187-05S1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10498150. Licensed CC0.

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