Projects / Programmes
Computational and experimental investigation of senescent cells modulation as a new tool to combat age-related diseases
| Code |
Science |
Field |
Subfield |
| 1.04.00 |
Natural sciences and mathematics |
Chemistry |
|
| Code |
Science |
Field |
| 1.04 |
Natural Sciences |
Chemical sciences |
senescent cells, senolytics, antiaging research, age-related diseases, molecular dynamics, QM/MM simulations, enzyme catalysis, virtual screening
Data for the last 5 years (citations for the last 10 years) on
April 23, 2024;
A3 for period
2018-2022
Data for ARIS tenders (
04.04.2019 – Programme tender,
archive
)
| Database |
Linked records |
Citations |
Pure citations |
Average pure citations |
| WoS |
414 |
10,890 |
9,398 |
22.7 |
| Scopus |
428 |
12,286 |
10,623 |
24.82 |
Researchers (11)
Organisations (2)
Abstract
Aging is considered a major risk factor for the development of many age-related diseases such as dementia, hypertension, atherosclerosis, cancer, autoimmune diseases and others. Numerous studies have shown that aging is not a programmed process and could be mitigated along with age-related diseases by properly planned external interventions. One of them is the modulation or removal of senescent cells, which stop in the G1 phase of the cell cycle in response to various stressors, express their specific phenotype and with age begin to accumulate in the body. The research field of cellular senescence is still in its infancy and therefore many questions remain unanswered, both regarding the mechanism of senescent cells formation and the reasons for their accumulation in later years. Nevertheless, compounds that affect senescence, also named senotherapeutics are being actively developed. These are dominated by senomorphics, which can modulate certain processes in senescent cells, most commonly the senescence-related secretory phenotype (SASP), and senolytics, which remove senescent cells from the body via selectively induced apoptosis. Some of these compounds have already made it to clinical studies to be assess as potential future therapeutics to tackle the age-related diseases in a more mechanistic way. In this project we will attempt to increase the understanding of mechanisms behind the senescent cells formation as well as try to modulate the number of senescent cells in the body with external molecules. In the first part , we will elucidate one of the potential mechanisms for senescent cell accumulation that inhibits the activity of natural killer (NK) cells and CD8+ T cells due to the increased presence of interactions between HLA-E/ß2m/peptide (present on senescent cells) and CD94/NKG2A (present on NK/CD8+ T cells) complexes using state-of-the-art molecular simulations. This will provide the theoretical background for possible further experimental research and enable targeted design of therapeutic interventions to modulate the inhibitory effect on NK and CD8+ T cells. In the second part, we will elucidate the enzymatic catalytic mechanism of DPP4 by quantum-classical (QM/MM) dynamics simulations in combination with enhanced sampling methods. From the detailed knowledge of the enzymatic catalytic mechanism and its critical structures, it will be possible to initiate design inhibitors for these states, thereby inhibiting the enzyme and potentially modulate the pathway of oxidative stress reduction. In the third part, we will employ similarity-based virtual screening of compound libraries to identify new chemical classes of senolytics and senomorphics whose efficacy will be experimentally characterized on senescent fibroblasts. This will allow the discovery of new chemical tools to study senescence, which could potentially be valuable in the development of new therapies for many age-related diseases. The knowledge gained in this project has a potential research breakthroughs and impact in both basic and applied scientific endeavors. First, it may inspire future biochemical, biological, and in vivo experiments aimed at unraveling the fundamental properties of senescent cells being one of the core hallmarks of the aging process. In addition to understanding the functional biology of senescent cells and the components involved in their accumulation/removal pathways, our study may provide information that can lead to the onset of novel biomedical strategies and interventions targeting age-related diseases in a more mechanistic way.
