# Molecular Determinants of Mitochondrial Genome Abundance and Integrity

> **NIH NIH K00** · MASSACHUSETTS GENERAL HOSPITAL · 2020 · $93,480

## Abstract

BEYOND INFECTION: INNATE IMMUNE RECEPTORS AS AN EMERGING BRAKE ON METASTASIS
ABSTRACT
Innate immune signaling is a key mammalian defense against pathogens. Importantly, these signaling
networks are critically linked to human disease even outside the realm of infections. This facet of innate
immunity remains largely elusive and forms the subject of my research. My thesis focuses on the
pseudokinase RNase L, which is most strongly activated during infection. RNase L is triggered by 2'-5'-linked
iso-RNAs, produced by oligoadenylate synthetases (OASs) upon sensing double-stranded RNA (dsRNA)
commonly thought to come from RNA viruses. RNase L is essential for coping with bacterial and viral
infections. RNase L is also a major regulator of cell cycle progression, differentiation, and apoptosis, processes
often misregulated in cancers. Notably, many RNase L mutations predispose men to an elevated risk of
inherited prostate cancer. Moreover, my preliminary results uncover that dampened RNase L expression
strongly correlates with increased breast cancer aggressiveness. The effect of RNase L on tumor suppression
is striking but its molecular mechanism is unclear. My work identifies the first cellular targets of human RNase
L outside infection, tackling a challenge faced since the discovery of RNase L in 1980. Serendipitously, RNase
L targets perfectly overlap with those of a well-established tumor-suppressor, miR-200, and one of their
common targets is the master regulator of metastasis, ZEB1. These results suggest a direct molecular
mechanism for the role of RNase L in controlling metastasis, which I seek to examine during my F99 phase. In
addition, I will isolate endogenous dsRNAs, predicted to be elevated in cancers, which can feed into the
OAS/RNase L axis. Thus, I will test if OASs are a dsRNA surveillance mechanism against not only viruses but
also cancer. This work will uncover the molecular mechanism for a major non-immune function of the
OAS/RNase L axis, informing novel diagnostic and therapeutic strategies against metastasis. My thesis
initiates me into the emerging field of innate immunity in cancer and seeds my postdoctoral research
directions. With rigorous training and an exciting potential to serve human health, I am on a perfect trajectory to
launch an independent career at the forefront of cancer immunology.

## Key facts

- **NIH application ID:** 9867656
- **Project number:** 5K00CA212468-04
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** Sneha Prakash Rath
- **Activity code:** K00 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $93,480
- **Award type:** 5
- **Project period:** 2019-02-06 → 2023-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9867656

## Citation

> US National Institutes of Health, RePORTER application 9867656, Molecular Determinants of Mitochondrial Genome Abundance and Integrity (5K00CA212468-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9867656. Licensed CC0.

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