# Role of prohibitin in ischemic brain injury

> **NIH NIH R56** · WEILL MEDICAL COLL OF CORNELL UNIV · 2020 · $499,205

## Abstract

ABSTRACT
The mitochondrial protein Prohibitin (PHB) is essential for life. Its importance to cellular activities
is attested by the fact that deletion of PHB is embryonic lethal in mice and that to date no mutation
has been found in the coding region of PHB in any disease conditions, indicating that PHB integrity
is essential and that somatic mutation is detrimental. PHB has been shown to be critical for
mitochondrial function in stress situations, as it is upregulated in ischemic preconditioning (IPC).
In the previous funding period, using neuron specific PHB transgenic mice, we demonstrated that
selective neuronal PHB expression leads to remarkable neuroprotection against middle cerebral
arterial occlusion (MCAO) induced brain injury. However, how this important protein is functionally
regulated in IPC, as well as how it is dysregulated in other neurological conditions, remain
surprisingly unknown. In exploring the mechanisms of PHB regulation, we discovered that nitric
oxide (NO) is required for both IPC and PHB upregulation. Therefore, we investigated the
interaction between NO and PHB and found that NO modifies PHB post-translationally, through
protein s-nitrosylation. In this renewal application, we propose to study the effects of PHB S-
nitrosylation and the mechanisms underlying functional regulation of PHB by NO. Our central
hypothesis is that PHB nitrosylation is critical for its neuroprotective function and that disturbances
of PHB nitrosylation is detrimental. We will use a mutant knockin mouse, in which the sole
cysteine residue of PHB protein is mutated so that PHB cannot be nitrosylated, and a PHB
neuronal knockout mouse, in which PHB deletion is complemented by AAV expressing wild type
or non-nitrosylated C69S mutant to analyze the mechanisms of NO regulation and the effects of
loss of PHB nitrosylation on PHB function, in IPC. Three specific aims will systematically test the
hypothesis. The results of the proposed studies will reveal a previously undescribed regulatory
mechanism of PHB and could benefit patients at risk of stroke and other neurological conditions.

## Key facts

- **NIH application ID:** 10201370
- **Project number:** 2R56NS067078-11A1
- **Recipient organization:** WEILL MEDICAL COLL OF CORNELL UNIV
- **Principal Investigator:** Ping Zhou
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $499,205
- **Award type:** 2
- **Project period:** 2009-09-15 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10201370

## Citation

> US National Institutes of Health, RePORTER application 10201370, Role of prohibitin in ischemic brain injury (2R56NS067078-11A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10201370. Licensed CC0.

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