SubsidieMeestersTargeting telomeric DNA damage response as a new strategy to fight immunosenescence and improve vaccine response
The project aims to evaluate the effectiveness of telomeric antisense oligonucleotides in rejuvenating the immune response and enhancing vaccine efficacy in aged mice.
Projectdetails
Introduction
The immune system is remodeled with age, going through a series of changes known as immunosenescence. These changes include:
- The involution of primary lymphoid organs
- The contraction of the immune repertoire
- A progressive lineage skewing towards the myeloid lineage
- A low-grade pro-inflammatory status
A consequence of immunosenescence impacting the morbidity and mortality of infectious diseases is a dramatically reduced vaccine response in the elderly. Thus, reducing the burden of immunosenescence has the potential to impact the effectiveness of vaccine response.
Telomere Dysfunction
An established hallmark and driver of age-associated functional decline is telomere dysfunction. Dysfunctional telomeres are actively transcribed to generate telomeric non-coding RNAs (tncRNA), which are essential to recruit DNA Damage Response (DDR) factors at damaged telomeres. This process fuels DDR and causes cellular senescence initiation and maintenance.
Telomeric Antisense Oligonucleotides
Sequence-specific telomeric antisense oligonucleotides (tASOs) target these tncRNAs and effectively inhibit DDR activation, ameliorating age-related phenotypes in mouse models.
Mouse Model
The telomerase-deficient (Terc-/-) mouse model causes telomere shortening and dysfunction, recapitulating features of immunosenescence, including:
- Immune system reactivity reduction
- Decreased long-term renewal of hematopoietic stem cells
- Decreased lymphocyte numbers
- Increased neutrophil count
tASOs treatment has a beneficial long-term effect in this model by decreasing immunosenescence and counteracting inflammation.
Future Plans
We now plan to test the efficacy of tASOs treatment on rejuvenating the immune system of aged wild type mice, which represents a physiological setting for aging.
Goals
The final goal will be to assess if tASOs impact vaccine response in both models:
- Young Terc-/- mice
- Aged WT mice
In summary, we plan to determine the efficacy of tASOs to improve immune responses, including vaccines, in the elderly.
Financiële details & Tijdlijn
Financiële details
| Subsidiebedrag | € 150.000 |
| Totale projectbegroting | € 150.000 |
Tijdlijn
| Startdatum | 1-9-2023 |
| Einddatum | 28-2-2025 |
| Subsidiejaar | 2023 |
Partners & Locaties
Projectpartners
- IFOM-ISTITUTO FONDAZIONE DI ONCOLOGIA MOLECOLARE ETSpenvoerder
Land(en)
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