Lung-protective mechanisms of metformin in TB

Ended Project Grant Awarded Last action

Award ID
R01HL152078
Recipient
Awarding agency
Obligated
$3,095,975

Award facts

Assistance listing
93.837 Cardiovascular Diseases Research
Completion date
Originally
Place of performance
Worcester, MA 01655, USA

Award details come from USAspending.gov.

Description

As the agency reported it.

Abstract
Tuberculosis (TB), caused by mycobacterium tuberculosis (MTB), remains a major global health threat. Challenges of compliance and toxicities of prolonged antimicrobial regimens and increasing drug resistance highlight the need for novel treatment approaches. Host-directed therapy (HDT) harnesses host-intrinsic mechanisms using small molecule drugs to accelerate sterilization and limit lung damage caused by host immunity. We reported that metformin reduced lung bacterial load and immune pathology in MTB-infected mice. Retrospective data from over half a million individuals treated for diabetes with metformin support the HDT potential of this drug. These studies reported lower rates of MTB infection and progression from latent to active TB, less cavitation and all-cause mortality, accelerated sputum conversion and less TB recurrence. The goal of this project is to discern the mechanisms of metformin HDT efficacy, focusing on inflammation and fibrosis. Our preliminary data suggest that metformin expands non-classical LY6CLO monocytes in an ampk-dependent manner. These cells are essential for host protection in innate "trained" immunity and they participate in tissue repair. LY6CLO monocytes produce CXCL10 that recruits CD8+CXCR3+ memory (TM) cells, which may restrict MTB replication in an antigen-specific and non-specific manner. Our data also suggest that metformin-mediated protection involves notch pathway modulation, with suppression of NOTCH1 that drives fibrosis and enhancement of NOTCH2 to regulates LY6CLO monocyte and CD8+ TM cell differentiation. Experiments in aim 1 will establish the requirement for ampk and notch signaling in the protective functions of metformin using the mouse aerosol TB model. Outcomes are lung bacterial load, immune pathology, lung tissue damage with collagen remodeling and transcriptomic and proteomic markers of fibrogenesis. Immunometabolic and epigenetic regulatory activities of metformin will be investigated in the context of TB-HDT. Experiments in aim 2 will establish the requirements for CD8+ TM cells and the CXCL10- CXCR3 axis in host protection and evaluate potential similarities and differences between metformin- educated CD8+ TM cells and virtual memory T cells. Both aims include validation studies using alternative mouse models (C3HEB/FEJ and collaborative cross) and DE-identified human plasma, blood RNA and pbmc samples from clinical TB studies having participants with or without metformin exposure. This project will produce new knowledge about the mechanisms of metformin TB-HDT efficacy that will support the design and interpretation of human clinical trials using metformin and might identify new targets for HDT agents having greater specificity, efficacy and tolerability than metformin.

Transactions

Action Obligated Date
Amendment -$7,122
Amendment $49,331
Amendment $555,000
Amendment $555,000
Amendment $63,760
Amendment $573,857
Amendment $64,787
Amendment $583,090
Amendment $65,825
Original award $592,447

Subawards

Subrecipient Amount Awarded
A*Star Infectious Diseases Labs A*STAR Infectious Disease Labs (ID Labs) will serve as a subcontract for the study entitled "Lung-Protective Mechanisms of Metformin in TB". Dr. Singhal has… $12,439
A*Star Infectious Diseases Labs $111,952

Quick answers

Who received award R01HL152078?

R01HL152078 was awarded to University Of Massachusetts Medical School by National Heart Lung and Blood Institute (National Institutes of Health) on February 2, 2021.

How much is award R01HL152078 worth?

$3,095,975 has been obligated on R01HL152078.

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