# Project 3. Defining the RNA processing and degradation pathways of Mtb.

> **NIH NIH P01** · WEILL MEDICAL COLL OF CORNELL UNIV · 2022 · $429,263

## Abstract

Project 3, Abstract
Transcript processing and degradation are key processes by which the cell regulates its functional capacity and
physiological state, yet little is known about how these pathways function in Mycobacterium tuberculosis (Mtb).
Mutations in components of the RNA processing and degradation machinery are associated with drug resistance
in clinical strains and with drug tolerance in mice and in vitro, highlighting the relevance of these pathways for
clinically important phenotypes. The lack of knowledge about the fundamental biology of mycobacterial RNA
metabolism, including pathway structure and functional consequences of these pathways, represent a barrier to
understanding clinically important routes to drug resistance. The proposed project addresses this gap by
elucidating the targets and functional relationships between the critical RNA processing and degradation
proteins, focusing on how these processes modify drug efficacy. The specific aims are to:
 1. Determine the physical and genetic interactions that define and organize RNA processing and
 degradation pathways.
 2. Define the targets of RNA degradation proteins that are associated with drug resistance.
 3. Determine the phenotypic consequences of perturbations to RNA processing pathways.
The project seeks to move from piecemeal efforts to a pathways-directed approach capable of elucidating the
consequences of complex processes important to adaptation to the host and to drug pressure. To achieve this,
the project leverages high-throughput methodologies and extensive collaboration with other projects and cores.
Biochemical approaches will be used to define the physical associations between degradation pathway
components and their target specificities; TnSeq to map pathway structure and its phenotypic consequences;
transcriptomics approaches to determine how RNA metabolism pathways shape the transcriptome; murine
models to interrogate the relationship between RNA processing mutants and drug efficacy in vivo; and metabo-
lipidomics approaches to determine the impact of RNA processing mutants on metabolic status and permeability.
Combining a variety of approaches and expertise in an intentional and systematic fashion will allow the project
to define the mechanisms and consequences of RNA processing and degradation in mycobacteria in a way that
has not previously been feasible. In the long term, the knowledge obtained will inform efforts to design more
effective diagnostics, drugs and regimens.

## Key facts

- **NIH application ID:** 10426181
- **Project number:** 5P01AI143575-03
- **Recipient organization:** WEILL MEDICAL COLL OF CORNELL UNIV
- **Principal Investigator:** SABINE EHRT
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $429,263
- **Award type:** 5
- **Project period:** 2020-06-12 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10426181

## Citation

> US National Institutes of Health, RePORTER application 10426181, Project 3. Defining the RNA processing and degradation pathways of Mtb. (5P01AI143575-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10426181. Licensed CC0.

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