# Novel approaches to identify regulators of Bak1 splicing

> **NIH NIH R21** · UNIVERSITY OF CALIFORNIA RIVERSIDE · 2020 · $452,852

## Abstract

The objective of this application is to unbiasedly identify regulators essential for programming intrinsic neuronal
resistance to apoptosis. Apoptosis is a ubiquitous regulated cell death pathway controlling cell turnover and
tissue homeostasis in metazoans. A longstanding issue is how neurons suppress apoptosis in favor of
longevity. Previous studies on neuronal regulation of apoptosis have focused on why and how extrinsic survival
cues help establish and maintain neural circuits through the control of cell death. While these inspiring studies
delineate how neurons compete for survival at the time of circuit formation, important questions remain
unresolved, i.e., whether neuronal apoptosis sensitivity is genetically determined. In our preliminary studies, we
have found that neuronal resistance to apoptosis is intrinsically programmed before circuit formation by
depletion of pro-apoptotic mitochondrial protein BAK1. We further found that BAK1 expression is controlled at
the RNA level through robust alternative splicing mechanisms. The critical question is: what factors program
Bak1 splicing? Identification of these factors will have significant impacts and enable new investigations of
neuronal cell death controls in various settings. The proposed study will generate new tools and develop robust
cell-based methods to systematically identify regulators of Bak1 splicing. We will integrate experimental and
computational approaches to accelerate discoveries that would otherwise be limited and less sensitive. Our
team has demonstrated successful collaborations researching cell death, neuronal survival, and RNA
molecular genetics in the brain, and expect the proposed research to be fruitful. By revealing novel regulatory
mechanisms of apoptosis and associated genetic factors, our findings may inform strategies for enhancing cell
survival and tackling neurodegenerative diseases. Completion of the proposed study will also provide proof-of-principle for our broadly applicable strategy to study any alternative exons.

## Key facts

- **NIH application ID:** 10040977
- **Project number:** 1R21NS117992-01
- **Recipient organization:** UNIVERSITY OF CALIFORNIA RIVERSIDE
- **Principal Investigator:** Liang Chen
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $452,852
- **Award type:** 1
- **Project period:** 2020-08-01 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10040977

## Citation

> US National Institutes of Health, RePORTER application 10040977, Novel approaches to identify regulators of Bak1 splicing (1R21NS117992-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10040977. Licensed CC0.

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