Sirtuins and host metabolism in TB pathogenesis and treatment

Ended Project Grant Awarded Last action

Award ID
R01HL153162
Recipient
Awarding agency
Obligated
$2,944,873

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), is the leading cause of death due to infection and many TB survivors are left with permanent lung impairment due to immune-mediated cavitation and fibrotic healing. Sirtuins (SIRTS) are a family of energy-sensing NAD+-dependent deacetylases that modify histones, transcription factors, metabolic enzymes, and other targets to defend starvation, restore homeostasis during stress, support mitochondrial integrity, and promote the resolution of inflammation. In published and unpublished preliminary studies, we found that levels of SIRT1 (the major cytosolic sirt) and SIRT3 (the major mitochondrial sirt) are downregulated in macrophages (MF) infected with mycobacterium tuberculosis (MTB). Preliminary data support a model in which SIRT1/3 axis suppression by MTB in MF alters the expression levels of genes in the tricarboxylic acid cycle, electron transport chain, and glycolytic pathway. This causes a shift from oxidative phosphorylation to glycolysis, increases production of mitochondrial reactive oxygen species (ROS), and impairs ROS scavenging. The result is increased mitochondrial stress and MF cell death. The glycolytic shift (warburg effect) rapidly enhances MF antimicrobial performance but at the expense of perturbing multiple SIRT1/3 regulated processes that lead to increased inflammation and TB disease severity with chronic infection. Studies in aim 1 build on and fill gaps in our preliminary data, with in vitro experiments investigating the mechanism of SIRT1/3 downregulation by MTB and the downstream effects on metabolic and epigenetic reprogramming. Aim 2 uses existing strains of SIRT1 and SIRT3 null mice, and other strains in development, for aerosol TB studies that will relate in vitro data from AIM1 to host defense at the systemic level in vivo. The project culminates with testing of several sirt agonists for host-directed therapy of TB. We predict that these agents will restore mitochondrial homeostasis, hasten lesion sterilization, and reduce pulmonary TB immune pathology. The effects of these agents on immunometabolic pathways in vivo will be interpreted in the context of in vitro data produced in aim 1. Our project addresses an important GAP in understanding the upstream triggers and downstream consequences of the warburg effect in TB while at the same time producing new knowledge about potential adjunctive treatments to improve TB treatment outcomes and reduce the burden of pulmonary impairment in TB survivors.

Transactions

Action Obligated Date
Amendment -$152,343
Amendment $49,712
Amendment $559,255
Amendment $559,255
Amendment $628,640
Amendment $636,398
Amendment $0
Original award $663,956

Subawards

Subrecipient Amount Awarded
A*Star Infectious Diseases Labs Infectious Diseases Labs (ID Labs) A*STAR will serve as a subcontract for the study entitled “Sirtuins and Host Metabolism in TB Pathogenesis and… $18,980
A*Star Infectious Diseases Labs $170,816

Quick answers

Who received award R01HL153162?

R01HL153162 was awarded to University Of Massachusetts Medical School by National Heart Lung and Blood Institute (National Institutes of Health) on April 9, 2021.

How much is award R01HL153162 worth?

$2,944,873 has been obligated on R01HL153162.

On GovTribe

See this award's full record

  • Every transaction and subaward
  • The recipient's other awards and teaming partners
  • Similar grant awards
  • Ask GovTribe AI about this award
Try for free Login