# Linking Mitochondrial Calcium to Histone Methylation Underlying Lung Regeneration

> **NIH NIH F30** · TEMPLE UNIV OF THE COMMONWEALTH · 2024 · $35,481

## Abstract

PROJECT SUMMARY/ABSTRACT
Chronic Respiratory Diseases (CRDs) are the third leading cause of death and disability in the United States,
with a significant impact on the sociobiological and economic health of the country. Many patients with CRDs
present with dysregulation of lung healing after injury. Therefore, there is an unmet need to better understand
the molecular mechanisms underlying lung regeneration in order to develop novel treatment strategies for
these patients. Most of the gas exchange region of the lung is lined by Alveolar Epithelial Type 1 (AT1) cells.
When these cells are damaged, Alveolar Epithelial Type 2 (AT2) cells activate, proliferate, and differentiate into
new AT1 cells to replace them. Failure of AT2-to-AT1 differentiation contributes to the pathogenesis of CRDs.
However, the mechanisms underlying this transition are not completely understood. Data suggest that
expression of Mitochondrial Calcium Uptake 1 (MICU1) protein, as well as a reduction of trimethylated histone
H3 residues lysine 9 (H3K9me3) and lysine 36 (H3K36me3), are both vital for AT2-to-AT1 differentiation. We
hypothesize that alterations in MICU1-dependent mitochondrial calcium uptake drive AT2 differentiation by
rewiring cellular metabolism to favor the accumulation of α-ketoglutarate at the expense of succinate, thereby
increasing the activity of α-ketoglutarate-dependent histone demethylases and promoting an AT1 pattern of
gene expression. Therefore, our specific aims are to: (1) Determine the distribution of H3K9me3 and
H3K36me3 marks across the genome, and their functional consequences, during AT2-to-AT1 cell
differentiation in AT2 wildtype and MICU1 knockout cells, and (2) Determine whether increased H3K9me3 and
H3K36me3 are responsible for the decreased AT2-to-AT1 differentiation capacity of AT2 MICU1 knockout
cells. Aim 1 will utilize CUT&RUN, ATAC-Seq, and RNA-Seq, while Aim 2 use CRISPR/Cas9 gene editing both
in vitro and in vivo. The proposed experiments will take place in the Center for Translational Medicine in the
Lewis Katz School of Medicine at Temple University, an institution with a track record of excellence in both
clinical medicine and scientific research. The training plan, developed by Co-Sponsors Drs. Tian and Elrod, will
be tailored to ensure success of the applicant, Morgan Pantuck, as she progresses through Temple's MD/PhD
program. Overall, this grant will provide an excellent training vehicle for the applicant while also increasing our
understanding of the molecular mechanisms underlying lung regeneration, supporting development of novel
treatments for CRDs.

## Key facts

- **NIH application ID:** 10901216
- **Project number:** 1F30HL174158-01
- **Recipient organization:** TEMPLE UNIV OF THE COMMONWEALTH
- **Principal Investigator:** Morgan Pantuck
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $35,481
- **Award type:** 1
- **Project period:** 2024-09-16 → 2027-09-15

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10901216

## Citation

> US National Institutes of Health, RePORTER application 10901216, Linking Mitochondrial Calcium to Histone Methylation Underlying Lung Regeneration (1F30HL174158-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10901216. Licensed CC0.

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