# Tip60, Ischemic Heart Disease and Regeneration

> **NIH NIH R01** · MEDICAL COLLEGE OF WISCONSIN · 2020 · $501,446

## Abstract

PROJECT SUMMARY
Tip60 protein, also known as Tat-interactive protein 60 kD, has been associated with induction of apoptosis,
the DNA damage response (DDR), and cell-cycle senescence -- functions that are not mutually exclusive -- in
cell-lines and in cancer cells. We have shown that Tip60 is a vital protein in the early embryo, and that it
undergoes a curious isoprotein shift as neonatal cardiomyocytes (CMs) enter replicative senescence, an event
that was recently shown to be induced by activation of the DDR in these cells. Although the heart is enriched
in Tip60 protein, its role in this organ remains unclear. A recent study using cultured neonatal CMs revealed
that ischemia increases Tip60 content and consequent apoptosis, effects that were prevented in Tip60-
depleted cells. This result is consistent with our previous finding in heterozygous Tip60+/- mice showing that
modest reduction of Tip60 protein in the adult heart caused release of CMs from cell-cycle arrest while
inhibiting apoptosis. Taken together, these findings suggest that reduction or inactivation of Tip60 should
enhance cardioprotection during ischemia, by suppressing CM death and permitting CM regeneration. To test
this possibility we have developed an animal model in which Tip60 can be conditionally depleted. Using these
mice we are addressing Specific Aims to test the twofold hypothesis that Tip60 is recruited to the telomere
during early neonatal stages to induce the DDR and replicative senescence in CMs (Aim 1), and that depletion
or inactivation of Tip60 in the adult heart confers cardioprotection from ischemia by inhibiting apoptosis and
permitting CM regeneration (Aim 2). Experimentally, the first Aim will determine whether Tip60 becomes
associated with the CM telomere at early neonatal stages, and whether its depletion reduces telomere length
and disrupts the DDR while extending the window of neonatal CM proliferation. The second Aim will determine
whether knockdown or transient inactivation of Tip60 in the ischemic adult heart inhibits apoptosis while
permitting CM regeneration. Fulfillment of this hypothesis will advance our understanding of how the post-
mitotic differentiated state of CMs is attained, while establishing Tip60 as a cardioprotective target.

## Key facts

- **NIH application ID:** 9837458
- **Project number:** 5R01HL131788-04
- **Recipient organization:** MEDICAL COLLEGE OF WISCONSIN
- **Principal Investigator:** JOHN A AUCHAMPACH
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $501,446
- **Award type:** 5
- **Project period:** 2016-12-15 → 2021-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9837458

## Citation

> US National Institutes of Health, RePORTER application 9837458, Tip60, Ischemic Heart Disease and Regeneration (5R01HL131788-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9837458. Licensed CC0.

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