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Exploring the link between senescence and inflammation

English title Exploring the link between senescence and inflammation
Applicant Ablasser Andrea
Number 188759
Funding scheme Project funding (Div. I-III)
Research institution Global Health Institute EPFL SV-DO
Institution of higher education EPF Lausanne - EPFL
Main discipline Immunology, Immunopathology
Start/End 01.04.2020 - 31.03.2023
Approved amount 756'000.00
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Keywords (3)

Inflammation; Senescence; Innate Immunity

Lay Summary (German)

Lead
In diesem Forschungsvorhaben möchten wir die gegenseitige Beziehung von Entzündung und Zellalterung untersuchen.
Lay summary
Das Alter ist ein eigenständiger Risikofaktor für eine Reihe von Erkrankungen. Ein hervorstechendes Charakteristikum des Alterungsprozesses ist die Anhäufung von sogenannten seneszenten Zellen. Seneszente Zellen zeichnen sich dadurch aus, dass sie die Fähigkeit zur Zellteilung verloren haben und, ferner, dass sie entzündliche Botenstoffe produzieren. Es wird angenommen, dass die subtile, jedoch andauernde entzündliche Reaktion, hervorgerufen durch Seneszenz, in wesentlichem Masse zu den degenerativen Erscheinungen des Alters und zahlreichen altersbedingten Erkrankungen beiträgt.
Entzündungsreaktionen entstehen typischerweise durch die Aktivierung des angeborenen Immunsystems. Ein wichtiger Mechanismus der Entzündungsreaktionen im Zuge der Seneszenz einleiten kann ist die Aktivierung eines bestimmen Signalweges des angeborenen Immunsystem, der genomische DNA erkennt. 
Das Ziel dieses Forschungsvorhaben ist es die Rolle dieses Signalweges in altersbedingter Seneszenz zu untersuchen und zu evaluieren inwiefern eine pharmakologische Unterbindung chronische Entzündungsreaktionen im Alter unterbinden kann. Ein weiteres Ziel ist es zu untersuchen wie sich eine gezielte Ausschaltung seneszenter Zellen im Alter auf chronische Entzündungserscheinungen auswirkt. 
Direct link to Lay Summary Last update: 10.06.2020

Responsible applicant and co-applicants

Employees

Associated projects

Number Title Start Funding scheme
159836 Exploring intracellular DNA sensing mechanisms triggered by Mycobacterium tuberculosis 01.06.2015 Project funding (Div. I-III)
155984 The role of intercellular signal transmission in innate immunity 01.04.2015 SNSF Starting Grants

Abstract

Old age is the predominant risk factor for a wide range of human diseases. Cellular senescence, a stress-induced irreversible growth arrest, is a hallmark of aging and has also been implicated in the pathogenesis of a range of aging-related diseases. Senescent cells display a distinctive secretory phenotype, referred to as the senescence-associated secretory phenotype (SASP), which is composed of cytokines, chemokines, growth factors, and proteinases. The inflammatory components of the SASP are speculated to critically influence the detrimental effects of senescent cells. Hence, therapeutic strategies that safely interfere with senescence, in particular with their inflammatory phenotype, are gaining considerable attention given their potential impact on improving late-life human health. Inflammation is typically associated with the activation of innate immune signaling pathways. Within senescent cells, we and others have recently discovered that aberrant self-DNA functions as a potent danger signal that activates the innate DNA sensor cGAS. On activation, cGAS produces the second messenger cGAMP, which engages the signaling molecule STING, ultimately leading to inflammatory responses and reinforcing senescence. These findings highlight the potential of cGAS and STING as promising therapeutic targets to disrupt the fatal responses of senescent cells. For the successful realization of such a pharmacological approach, however, a better understanding of the links between senescence and inflammation is imperative. The overarching goal of this proposal, which is divided in 3 Aims, is to mechanistically characterize the links between inflammation and cellular senescence. In Aim 1 we will systematically map signaling networks that are influenced by the activity of the cGAS-STING pathway throughout distinct stages of senescence. In Aim 2 we will characterize the effect of cGAS and STING in promoting senescence-associated disease and adverse phenotypes associated with the natural aging process. In Aim 3 we will comprehensively study cellular senescence at single-cell resolution to reveal time- and context-dependent subtypes of inflammatory senescent states. All in all the studies proposed here will uncover fundamental new mechanisms that determine the inflammatory behavior of senescent cells. Insight gained from this effort has the potential to provide new molecular targets for treating senescence-associated diseases and for promoting healthy aging.
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