# Exploring the use of conplastic mice as a model of risk stratification of coronavirus susceptibility

> **NIH NIH R01** · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · 2021 · $372,259

## Abstract

This application focuses on the observation that we and others have found that the mitochondrial unfolded protein
(UPRmt) leads to the activation of the innate immune system. More specifically, our group has identified two axes
of the UPRmt, one regulated by the mitochondrial sirtuin SIRT3, a longevity gene, and another regulated by the
estrogen receptor alpha (ERα), a major driver of sexual dimorphism. In addition, we reported that mitochondrial
DNA (mtDNA) profoundly influences the ability of cells to activate the UPRmt. We found that variations in mtDNA
sequence that are within the same range as variations observed between mtDNA haplotypes in the human
population, are sufficient to define whether the UPRmt is activated or not. Therefore, the premise of this
application is that the UPRmt may provide a mechanistic explanation to the epidemiology of COVID19 at three
levels. First, why it affects more severely elderly individuals; we hypothesize that the decline in SIRT3 during
aging weaken the ability to induce the UPRmt and consequently, the innate immune system. Second, why males
are more affected; we hypothesize that the inability to activate the ERα axis of the UPRmt in males contributes
to their increased sensitivity due to a weaker innate immune response. Third, why some individuals are
asymptomatic while others die: we hypothesize that individuals carrying UPRmt-activating mtDNA maybe those
who are asymptomatic, while those individuals who carry mtDNA that do not lead to the activation of the UPRmt
maybe those who develop severe symptoms. The hypotheses proposed in this supplement are further supported
by recent findings from the parent award focusing on the UPRmt in conplastic mice, which were found to be
healthier and live longer. These mice share the same nuclear genome but only differ in their mitochondrial
genomes. Most recently, we found that the conplastic females activate the UPRmt and that the gene expression
profiles in female conplastic mice is enriched in immune and anti-viral genes, while conplastic male mice do
not. These results strongly support our hypotheses and raise the possibility that the conplastic mice may
represent a unique mouse model to dissect several aspects of the epidemiology of COVID19. Additionally, our
RNAseq analysis identified clinically approved drugs that mimic the genetic signatures in female conplastic mice,
therefore offering potential pharmacological means to modulate immune profiles. Based on these observations
we propose: Specific aim 1: Compare the susceptibility to coronavirus infections between wild-type and
conplastic mice in both sexes. Specific aim 2: Test if pharmacological intervention that mimics the genetic
signature of conplastic females protects wild-type mice from adverse effect of coronavirus infection.

## Key facts

- **NIH application ID:** 10162776
- **Project number:** 3R01AG059635-04S1
- **Recipient organization:** ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
- **Principal Investigator:** DORIS A GERMAIN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $372,259
- **Award type:** 3
- **Project period:** 2018-08-01 → 2023-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10162776

## Citation

> US National Institutes of Health, RePORTER application 10162776, Exploring the use of conplastic mice as a model of risk stratification of coronavirus susceptibility (3R01AG059635-04S1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10162776. Licensed CC0.

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