# Systems biology analysis of RNA-binding protein aggregation during cellular aging

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2024 · $453,193

## Abstract

Project Summary
RNA-binding proteins (RBPs) play key roles in regulating gene expression and many cellular functions. A lot of
RBPs are aggregation-prone due to their low complexity, prion-like domains. While naturally-occurring
aggregation of RBPs is important for the compartmentalized control of RNA metabolism, aberrant aggregation
is detrimental and is associated with many diseases, in particular, age-related diseases such as
neurodegenerative diseases and cancers. However, a systematic analysis of RBP aggregation and its functional
consequences during aging remains lacking. Here we propose to conduct a systems biology analysis of age-
dependent RBP aggregation using the replicative aging of S.cerevisiae as a model system. Our initial screen
has identified positive RBP candidates that aggregate upon aging-related perturbations. Building upon these
findings, we will combine innovative microfluidics with single-cell imaging technologies to systematically
characterize these RBP aggregates during aging and to evaluate how these aggregates influence gene
expression, aging phenotypes and the lifespan of individual living cells. In Aim 1, we will systematically
characterize each of the identified RBPs that aggregate during aging. We will determine the biophysical and
biochemical properties, material state and phase transition of RBP aggregates at different stages of the lifespan,
which will provide important clues about how these aggregates influence cell physiology during aging. In Aim 2,
we will investigate the interplay between RBP aggregation and cellular aging, focusing on how aggregation of
RBPs is regulated by conserved aging-related pathways or factors, and how these aggregates contribute to age-
dependent cellular changes and the final lifespan. In Aim 3, we will evaluate how RBP aggregation contributes
to the proteomic changes during aging. We will use a newly-developed high-throughput microfluidic platform to
identify target genes that are regulated by RBP aggregation and will examine their influences on aging,
establishing the functional links among RBP aggregation, proteomic changes and aging phenotypes. Finally, we
will integrate all the data generated in Aims 1, 2 and 3, delineate a systems-level regulatory network of RBP
aggregation during yeast replicative aging, and develop a dedicated website for sharing the data to the scientific
community. The RBP-regulated network will provide mechanistic insights into the causes, control and
consequences of pathological RBP aggregation in aging and will be used to guide the design of new hypotheses
and experiments, laying the foundation for the development of therapeutic and preventive strategies towards
age-associated diseases.

## Key facts

- **NIH application ID:** 10900577
- **Project number:** 5R01AG068112-04
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** Nan Hao
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $453,193
- **Award type:** 5
- **Project period:** 2021-09-15 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10900577

## Citation

> US National Institutes of Health, RePORTER application 10900577, Systems biology analysis of RNA-binding protein aggregation during cellular aging (5R01AG068112-04). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10900577. Licensed CC0.

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