Innovating Works

IMPACT

Financiado
Imidazole propionate and fibrosis in cardiometabolic diseases
Fibrosis is a pathological feature caused by excessive extracellular matrix secretion, resulting in scar tissue that causes thickening and loss of tissue mobility, culminating in impaired organ function. It is a common feature of... Fibrosis is a pathological feature caused by excessive extracellular matrix secretion, resulting in scar tissue that causes thickening and loss of tissue mobility, culminating in impaired organ function. It is a common feature of heart failure and non-alcoholic steatohepatitis and an important determinant of morbidity and mortality. However, relatively little is known about the underlying aetiology. We and others have mapped alterations in the gut microbiota in different cardiometabolic diseases, focusing on the functions performed by the microbiota. IMPACT builds on our work showing that humans with type 2 diabetes have high plasma levels of the microbial metabolite imidazole propionate (ImP) and that ImP impairs insulin signalling through p38gamma. We also resolved the X-ray crystal structure of urocanate reductase (UrdA), the bacterial enzyme responsible for ImP production. Our recent work showed that ImP is more strongly associated with heart failure and that treatment of mice with ImP promotes both cardiac and liver fibrosis, consistent with studies showing that p38gamma signalling is implicated in fibrosis development. IMPACT will first use state-of-the-art clinical assessments to determine how circulating levels of ImP correlate with fibrosis in heart and liver. Second, we will explore the kinetics by which ImP induces fibrosis in mice and how this process is associated with immune cell infiltration and disease progression. Third, to provide mechanistic understanding, we will perform similar experiments in mice lacking key target signalling components (e.g., p38gamma), combined with single cell sequencing that will guide us in producing tissue-specific knockouts to elucidate the cellular cross-talk. Fourth, we will generate UrdA inhibitors and test their potential to reduce ImP production in isolated bacteria, complex microbial communities, and colonised mice. Thus, IMPACT has the potential of generating new therapies to diseases with unmet clinical needs. ver más
31/07/2028
2M€
Duración del proyecto: 60 meses Fecha Inicio: 2023-07-19
Fecha Fin: 2028-07-31

Línea de financiación: concedida

El organismo HORIZON EUROPE notifico la concesión del proyecto el día 2023-07-19
Línea de financiación objetivo El proyecto se financió a través de la siguiente ayuda:
ERC-2022-ADG: ERC ADVANCED GRANTS
Cerrada hace 2 años
Presupuesto El presupuesto total del proyecto asciende a 2M€
Líder del proyecto
GOETEBORGS UNIVERSITET No se ha especificado una descripción o un objeto social para esta compañía.
Perfil tecnológico TRL 4-5