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Age-related changes of the liver circadian oscillator

English title Age-related changes of the liver circadian oscillator
Applicant Ripperger Jürgen A.
Number 152792
Funding scheme Project funding (Div. I-III)
Research institution Division de Biochimie Département de Biologie Université de Fribourg
Institution of higher education University of Fribourg - FR
Main discipline Molecular Biology
Start/End 01.04.2014 - 31.03.2016
Approved amount 244'329.00
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All Disciplines (3)

Discipline
Molecular Biology
Biochemistry
Genetics

Keywords (4)

gene regulation; photoperiod; aging; circadian oscillator

Lay Summary (German)

Lead
Viele metabolische und physiologische Prozesse verändern sich mit dem Alter. Letztendlich vereinbaren sich diese Veränderungen nicht mit dem Überleben. Allerdings ist der Übergang vom normalen Altern zu diesen Veränderungen nicht richtig verstanden. In diesem Projekt verfolgen wir die Reifung des zirkadianen Oszillators in der Leber um diesen Übergang besser zu verstehen.
Lay summary

Inhalte und Ziele des Forschungsprojekts

 

In diesem Projekt versuchen wir neue Erkenntnisse zu gewinnen, indem wir die Reifung des zirkadianen Oszillators in der Mausleber untersuchen. Der zirkadiane Oszillator bildet eine Art von innerer Uhr, die den Metabolismus und die Physiologie eines Organismus mit der Umwelt synchronisiert. Es handelt sich um einen äusserst robusten Mechanismus, der normalerweise nur wenig von äusseren Faktoren beeinflusst wird. Deshalb fanden wir es eigenartig, dass sich die verschiedenen Teile des zirkadianen Oszillator unterschiedlich mit dem Alter der Maus verändern. Wir erwarten, dass eine genaue Untersuchung dieser Diskrepanz uns neue Erkenntnisse über die verschiedenen Schritte des natürlichen Alterungsprozesses liefern wird. Idealerweise würden wir auch eine Idee dafür bekommen, was letztendlich dazu führt, dass die normalen Funktionen des Organismus ihre Aufgaben nicht mehr erfüllen können.

 

Wissenschaftlicher und gesellschaftlicher Kontext

 

Das Projekt befasst sich mit Grundlagenforschung. In den letzten Jahrzehnten ist die Lebenserwartung der Bevölkerung gestiegen. Obwohl eine erfreuliche Entwicklung, ergeben sich doch sozioökonomische und gesundheitspolitische Probleme für die Gesellschaft. Eine Vielzahl von Theorien versucht zu beschreiben, warum die normalen Vorgänge im Körper sich im Alter so weit verändern, dass sie das Überleben der betroffenen Personen beeinträchtigen. Allerdings stehen uns nicht viele Informationen über die molekularen Ursachen und vor allem über die Geschwindigkeit des Alterungsprozesses zur Verfügung. Mit dem neuen Modelsystem werden wir hoffentlich auch für den Menschen relevante Erkenntnisse gewinnen können.

 

Direct link to Lay Summary Last update: 12.05.2014

Responsible applicant and co-applicants

Employees

Publications

Publication
Single-cell transcriptomics allows novel insights into aging and circadian processes
Fonseca Costa Sara S, Robinson-Rechavi Marc, Ripperger Jürgen A (2020), Single-cell transcriptomics allows novel insights into aging and circadian processes, in Briefings in Functional Genomics, elaa014.
The Circadian Clock and the Aging Process
Hui Ka Yi, Ripperger Jürgen A. (2018), The Circadian Clock and the Aging Process, Elsevier, The Netherlands, 1067-1081.
Internal normalization of nascent RNA sequencing experiments to identify age-related changes of the mouse liver transcriptome
Fonseca Costa Sara S, Ripperger Jürgen A (2017), Internal normalization of nascent RNA sequencing experiments to identify age-related changes of the mouse liver transcriptome, in Genomics and Computational Biology, 3(2), 34-34.
Normalisation against Circadian and Age-Related Disturbances Enables Robust Detection of Gene Expression Changes in Liver of Aged Mice
Fonseca Costa Sara S., Wegmann Daniel, Ripperger Jürgen A. (2017), Normalisation against Circadian and Age-Related Disturbances Enables Robust Detection of Gene Expression Changes in Liver of Aged Mice, in PLOS ONE, 12(1), e0169615-e0169615.
Grab the wiggly tail: new insights into the dynamics of circadian clocks
Hui Ka Yi, Ripperger Jürgen A (2015), Grab the wiggly tail: new insights into the dynamics of circadian clocks, in Nature Structural & Molecular Biology, 22(6), 435-436.
Impact of the Circadian Clock on the Aging Process
Fonseca Costa Sara S., Ripperger Jürgen A. (2015), Impact of the Circadian Clock on the Aging Process, in Frontiers in Neurology, 6, 43.

Collaboration

Group / person Country
Types of collaboration
Daniel Wegmann, University of Fribourg, Schweiz Switzerland (Europe)
- Publication
Urs Albrecht, University of Fribourg Switzerland (Europe)
- Publication
- Research Infrastructure

Scientific events



Self-organised

Title Date Place
4th Swiss Chronobiology Meeting 03.09.2015 Fribourg, Switzerland
3rd Swiss Chronobiology Meeting 04.09.2014 Fribourg, Switzerland

Associated projects

Number Title Start Funding scheme
135587 Adjustment of the mouse liver transcriptome to the photoperiod 01.04.2011 Project funding (Div. I-III)

Abstract

2.1 SUMMARY: Age-related changes of the liver circadian oscillator2.1.1 BACKGROUNDAging alters a variety of cellular and physiological processes, which increases the probability of disease and finally death. Although our knowledge regarding recently defined ‘hallmark processes of aging’, which adversely affect cellular and physiological processes (e.g., genome stability or mitochondrial function), the overall picture is less clear. In particular, the transition from primary aging, i.e. age-related changes that are not harmful to the organism, to secondary aging or senescence may either be programed or stochastic. To address this issue, it would be useful to have easy-to-follow primary aging programs at our disposal from which deviations can be monitored over time. Previously, we investigated the behavior of the circadian oscillator in mouse liver with age and found it to behave as a robust primary aging program. An auto-regulatory feedback loop comprised of the circadian output factors of the PAR-bZip family appears to govern age-related increases in amplitude and magnitude of circadian oscillations. However, it is not yet clear how this feedback loop is regulated and how many target genes are affected. Hence, the analysis of the circadian oscillator may provide new insights into aging.2.1.2 WORKING HYPOTHESISPAR-bZip factors govern age-related changes of the liver transcriptome.2.1.3 SPECIFIC AIMSI. Analysis of the flexibility of the circadian oscillatorIt was found that electro-physical properties of neurons in aged mice mimic those of mice kept in long photoperiods. We are interested in the flexibility of the circadian oscillator in the liver in response to the photoperiod and want to compare the circadian oscillator network in both conditions (i.e. photoperiod and age). We will measure mRNA and protein accumulation at two hours resolution to determine phase and amplitude of the circadian oscillator. Using affected mouse mutant strains in their circadian oscillator, it will be possible to compare the underlying process permitting flexibility in either situation.II. Analysis of the impact of circadian PAR-bZip factorsPreliminary data suggests that an auto-regulatory feedback loop generated by PAR-bZip factors causes age-related transcriptional changes in the liver. ChIP experiments with antibodies for PAR-bZip factors revealed an unexpected high number of genomic binding sites. Hence, PAR-bZip factors may act as universal amplifiers of transcription similar to c-Myc, and thus may affect the entire liver transcriptome. This new concept will be verified by additional ChIP-sequencing experiments using chromatin derived from mice of different age and functional characterization of PAR-bZip factor mouse mutant strains.2.1.4 SIGNIFICANCEThe increase of elder persons and the emergence of age-related diseases are upcoming issues for our society. Here we analyze age-related changes of the liver circadian oscillator as a starting point to understand the transition from healthy primary aging to damaging secondary aging.
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