[R01] Regulation of disease progression by ER stress
Ente: National Heart Lung and Blood Institute
Scadenza: 2029-05-31
Importo max: 650.456 EUR
Paese: US
Descrizione
There is no current curative therapy for asbestos-induced fibrosis. Recruited monocyte-derived
macrophages (MDMs)play a critical role in the pathogenesis of asbestos-induced disease progression.
The activation of MDMs is dependent on their metabolic profile. Metabolic reprogramming is a key feature
in macrophage activation; however, the regulation of metabolic reprogramming of macrophages in
asbestos-induce fibrosis progression is poorly understood. Other than causing an alternative phenotype
in certain macrophages, little is known about ER stress and UPR in lung macrophages. The effect of ER
stress and UPR on metabolic reprogramming in lung fibrosis has not been investigated in any cell type,
including lung macrophages. Our preliminary data show that lung macrophages from asbestosis subjects
have activation of PERK (p-PERK) and absence of p-IRE1a. Asbestosis subjects also express
significantly more PGC-1a in lung macrophages than normal subjects. Silencing PERK (Eif2ak3)
completely abrogated PGC-1a expression in the nucleus. Asbestosis lung macrophages have increased
metabolites associated with metabolic reprogramming to OXPHOS. Over expression of PERK in
macrophages markedly increased OCR, while a dominant negative PERK reduced OCR. Moreover, mice
harboring a conditional deletion of Eif2ak3 in MDMs are protected from asbestos-induced lung fibrosis.
Based on these observations, we hypothesize that macrophage ER stress and UPR have a crucial role
in asbestosis progression by increasing PERK-mediated metabolic reprogramming. Aim 1 will determine
if metabolic reprogramming has a role in asbestosis progression using mice with a conditional deletion
of PERK (Eif2ak3) in monocyte-derived macrophages or with a PERK inhibitor. In Aim 2, we will
determine the mechanism(s) by which ER stress and UPR activates PGC-1a to mediate metabolic
reprogramming. Aim 3 will determine if activation of PERK is required for FAO in lung macrophages from
subjects with asbestos-induced toxicity. The studies in this proposal will provide: (a) new insights into the
effect of ER stress and UPR in progression of fibrotic disease; (b) an understanding of the molecular
mechanism(s) by which ER stress and UPR modulate lung macrophages to undergo metabolic
reprogramming; and (c) proof-of-concept by targeting UPR genetically to disrupt metabolic
reprogramming and regulate or reverse established asbestos-induced fibrosis.
Istituzione: UNIVERSITY OF ALABAMA AT BIRMINGHAM
PI: A BRENT CARTER
Progetto: 5R01HL176770-02
Settori: National Heart Lung and Blood Institute
Vai al bando originale
Registrati gratis su Bandolo per trovare bandi compatibili con la tua azienda.