# Heat Shock Factor mediates actin phosphorylation in tissue integrity and age

> **NIH NIH R01** · UT SOUTHWESTERN MEDICAL CENTER · 2021 · $332,100

## Abstract

Project Summary/Abstract
Aging involves the gradual decay of tissues, organs and organ systems. Early in this process, impermeability or
selective permeability of tissues deteriorates and gives rise to increasing organ dysfunction. This phenomenon
has been termed barrier dysfunction, yet the molecular mechanisms, which drive tissue “leakiness” and
contribute to organ aging are unclear. To interrogate the underlying mechanism, we examine the aging intestine
of the nematode, C. elegans, to determine how resiliency of the intestinal barrier withstands the test of time.
Preliminary screens from my lab have linked age regulation by the Heat Shock transcription Factor, HSF-1, with
the activity of the intestine-specific actin protein, ACT-5. Although expressed in a small number of cells and
comprising less than 2% of total worm actin, ACT-5 plays an essential role in intestinal and organismal aging.
Through the proposed five-year research period, we aim to understand how age-related decline in HSF-1 activity
contributes to tissue dysfunction and animal aging. In particular, we will characterize the molecular mechanism
of age progression in which HSF-1 dysregulation impairs cellular architecture and intestinal physiology. We
speculate that age-associated decline in HSF-1 activity impairs specialized actin networks in intestinal
epithelium, which ultimately compromise vesicular traffic, cell-cell junctional integrity and tissue barrier
maintenance. We have already identified the stress-activated JUN kinase, KGB-1, as a repressed transcriptional
target of HSF-1, which catalyzes phosphate addition to the ACT-5 protein within its binding site for the actin
filament stabilizing Troponin complex. Accumulation of phosphorylated ACT-5 at serine residue 232 dramatically
influences the structural integrity of the apical terminal web and vesicular transport across it. Overall, the
proposed research will uncover a phosphorylation-dependent actin relaxation mechanism under HSF-1 control,
which facilitates vesicular transport across dense, actin-rich “roadblocks” while still maintaining their structural
rigidity and cellular architecture.

## Key facts

- **NIH application ID:** 10104419
- **Project number:** 5R01AG061338-03
- **Recipient organization:** UT SOUTHWESTERN MEDICAL CENTER
- **Principal Investigator:** Peter Mahan Douglas
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $332,100
- **Award type:** 5
- **Project period:** 2019-04-01 → 2024-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10104419

## Citation

> US National Institutes of Health, RePORTER application 10104419, Heat Shock Factor mediates actin phosphorylation in tissue integrity and age (5R01AG061338-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10104419. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*