# Unfolded Protein Response Activation as a Determinant of the Host Response to M. tuberculosis

> **NIH NIH F32** · UNIV OF MASSACHUSETTS MED SCH WORCESTER · 2024 · $81,364

## Abstract

It is estimated that roughly 10 million people fall ill with TB annually. Even when successfully cured with
antibiotics, TB patients often suffer from permanently impaired lung function resulting from infection associated
inflammation. Host directed therapies that limit nonproductive inflammation represent a promising tool to improve
disease outcomes. Development of these therapies has been hindered by the extent of heterogeneity observed
in individual responses to Mtb infection. To overcome this limitation, novel approaches must be utilized to
understand the pathways underlying these variable outcomes. The applicant proposes the use of the genetically
diverse collaborative cross (CC) panel of inbred recombinant mouse strains to characterize the features
underlying variable responses to infection. Preliminary studies leveraging the diversity of the CC founder strains
revealed that variability in unfolded protein response (UPR) activity may underlie the heterogeneity in immune
responses to Mtb infection. The UPR is a mechanism for ensuring endoplasmic reticulum homeostasis and
consists of three distinct signaling pathways that initiate complementary responses. The activity of these
pathways is influenced by a variety of cell stress, homeostatic, and pathogen sensing pathways, emphasizing
the UPRs identity as a convergence point downstream of many potential sources of host variation. This proposal
aims to detail the contribution of UPR activity to myeloid responses to Mtb and to determine the feasibility of
targeting the individual UPR pathways for therapeutic intervention. The experiments proposed in aim 1 will
identify downstream correlates of UPR activity during infection and assess the contribution of the UPR pathways
to transcriptional response heterogeneity using single cell RNAseq technology. The studies described in aim 2
will characterize the consequences of chemical and genetic inhibition of UPR pathways on macrophage functions
during Mtb infection. Aim 3 will assess the impact of myeloid UPR pathway activity on disease progression
following pulmonary Mtb infection using a combination of genetics- and inhibitor- based approaches. Together,
these studies will provide insights regarding immune response heterogeneity and the contribution of the UPR
pathways to Mtb infection outcomes. The applicant will carry out the proposed studies as part of the Sassetti
research group at the University of Massachusetts Chan Medical School. This environment will provide them
with the facilities necessary to complete their studies, and input from a collaborative group of scientists with
expertise in relevant fields including immunology and bacteriology. By completing the proposed studies, the
applicant will gain experience in a variety of experimental techniques, including single cell RNAseq, and flow
cytometry. Additionally, through the training detailed in the proposal, the applicant will develop the professional
and communication skills necessary for suc...

## Key facts

- **NIH application ID:** 10887406
- **Project number:** 5F32AI176787-02
- **Recipient organization:** UNIV OF MASSACHUSETTS MED SCH WORCESTER
- **Principal Investigator:** Ryan Harold Finethy
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $81,364
- **Award type:** 5
- **Project period:** 2023-06-01 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10887406

## Citation

> US National Institutes of Health, RePORTER application 10887406, Unfolded Protein Response Activation as a Determinant of the Host Response to M. tuberculosis (5F32AI176787-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10887406. Licensed CC0.

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