RXR/pparg heterodimer agonists for treating virus-induced acute lung injury

Ended Project Grant Awarded Last action

Award ID
R03AI186104
Recipient
Awarding agency
Obligated
$213,810

Award facts

Assistance listing
93.855 Allergy and Infectious Diseases Research
Completion date
Place of performance
Maryland, USA

Award details come from USAspending.gov.

Description

As the agency reported it.

Abstract
Macrophages (MΦ) respond to pathogens, tissue damage, and host-derived mediators by differentiating into distinct functional phenotypes that mediate host innate immune responses. "classically activated" (M1) MΦ are highly microbicidal, yet their inflammatory products also damage host tissue. In contrast, "alternatively activated" (M2) MΦ subsets, including IL-4- and IL-13-induced "M2A MΦ," resolve tissue damage through anti-inflammatory mechanisms. The blanco laboratory has worked to study host responses to respiratory syncytial virus (RSV) and influenza, significant causes of severe lower respiratory tract infection. In wild-type (WT) mice, RSV infection elicits an early, transient M1 MΦ response in the lung followed by a sustained period of M2 MΦ predominance, and ultimately, resolution of lung pathology. RSV-infected IL-4RA-/- mice, whose MΦ lack a common receptor chain for IL-4 and IL-13, fail to differentiate into M2A MΦ and exhibit greatly enhanced lung pathology that is overcome by adoptive transfer of WT MΦ that differentiate into M2A MΦ. However, influenza infection fails to elicit a sufficient M2A MΦ response to override a strongly inflammatory M1 MΦ response, resulting in severe lung pathology. The transcription factor peroxisome proliferator-activated receptor gamma (pparg), a nuclear hormone receptor (NHR) required for M2A MΦ differentiation, forms heterodimers with another NHR, retinoid x receptor (RXR), and binds sites within M2A MΦ gene promoters to activate transcription. We found that therapeutic treatment of influenza-infected mice or cotton rats with the pparg agonist ligand, pioglitazone, suppressed M1 MΦ gene expression, enhanced M2A MΦ differentiation, protected mice against influenza- induced lethality, and mitigated lung pathology and inflammatory mediator production in both mice and cotton rats. Treatment of WT MΦ with IL-4 in the presence of RXR ligand, in combination with pparg ligand, synergized for induction of the prototype M2A marker, arginase 1, at the level of mrna and protein, suggesting that the RXR agonist may exert additional therapeutic effects in vivo by enhancing M2A MΦ differentiation. Our central hypothesis is that attaining the appropriate balance between these two opposing innate MΦ responses, M1 and M2, is key to development of efficacious therapies for viral-induced acute lung injury. This hypothesis will be tested initially by screening RXR ligands that were previously used in vivo to identify the most potent IL-4 CO- activator(s) of M2A MΦ in the absence or presence of pparg ligand. The therapeutic efficacy of lead pparg/RXR ligand combinations will be tested on influenza- or RSV-infected cotton rats, a rodent model that is uniquely susceptible to non-adapted strains of RSV and influenza. Completion of these studies is expected to provide strong evidence for the efficacy of new therapies against viral-induced lung inflammation based on our ground- breaking results showing a synergistic MΦ response to liganded RXR in the presence of pparg ligands.

Transactions

Action Obligated Date
Amendment -$2,570
Amendment $72,930
Amendment $7,550
Amendment $67,950
Original award $67,950

Quick answers

Who received award R03AI186104?

R03AI186104 was awarded to Sigmovir Biosystems, Inc. by National Institute of Allergy and Infectious Diseases (National Institutes of Health) on August 1, 2024.

How much is award R03AI186104 worth?

$213,810 has been obligated on R03AI186104.

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