CarboPore · Deciphering the mechanism of cellular aging: interaction of oxidatively damaged proteins with the cellular membranes
Horizon 2020 — Marie Skłodowska-Curie Actions
- Duration
- 2020-04-01 → 2023-03-31
- EU contribution
- €147,464
- Participants
- 1
- Scheme
- MSCA-IF
Lines connect the coordinator with its partners.
Results in brief
Deciphering the mechanism of cellular aging: interaction of oxidatively damaged proteins with the cellular membranes
Aging is a physiological process characterized by a progressive deterioration of organismal functions. As such, aging is a major risk factor for death and chronic conditions such as neurodegeneration, cancer, diabetes, arthritis, and cardiovascular diseases. Since the portion of elderly individuals in the human population has been rapidly increasing, healthy aging has become one of the most important goals and challenges of the contemporary society. However, despite extensive research, etiology and the mechanisms of aging remain some of the greatest mysteries in biology. In this project we have explored the molecular mechanisms of aging with the ultimate goal to set basis for development of treatments that would attenuate aging and delay the onset of age-related diseases. Our work was based on a concept that cumulative oxidative damage to proteins leads to age-associated cellular dysfunction. In particular, our goal was to test a hypothesis that the oligomers and aggregates formed by the oxidized proteins compromise the integrity of cellular membranes. The objectives of the project were the following: 1) to characterize the aggregates formed by the oxidized proteins; 2) to assess their interaction with the biological membranes and their ability to perforate the membranes; 3) to evaluate their cellular toxicity; and 4) to identify molecules that could either prevent the formation of the toxic aggregates, or protect the membranes from such aggregates. To that end, we used interdisciplinary approaches that included advanced imaging techniques – atomic force microscopy (AFM), stimulated emission depletion microscopy (STED) and Fourier transform infrared (FTIR) microscopy and spectroscopy, mass spectrometry (MS) and various biochemical techniques.
Data: CORDIS, © European Union
Project objective
Aging is one of the greatest mysteries in biology and a considerable contemporary societal challenge. Despite extensive research, the etiology of aging remains poorly understood. Most current theories focus on DNA damage as the root cause of aging. However, this view has been challenged by discovery that oxidative damage to proteins alone is sufficient to recapitulate molecular and cellular hallmarks of aging. In this project, we aim to elucidate the mechanism through which oxidatively damaged/carbonylated proteins lead to age-associated cellular dysfunction. Since misfolded, oxidatively damaged proteins form aggregates, and protein aggregates contribute to aging of various tissues, as well as lead to damage of cellular membranes, we hypothesize that age-associated increase in oxidative damage to proteins binding of the resulting protein aggregates to cellular membranes lead to membrane damage and permeabilization. To test this hypothesis, we will characterize oxidatively damaged oligomers and aggregates and assess their association with cellular membranes. Membrane damage will be evaluated upon its exposure to oxidized oligomers in vitro, using artificial lipid vesicles, and in living bacterial and mammalian cells. Interdisciplinary approaches will be used, including advanced imaging techniques such as atomic force microscopy, stimulated emission depletion microscopy and Fourier transform infrared microscopy and spectroscopy, mass spectrometry and various biochemical techniques. During the fellowship, the applicant will acquire skills necessary for reaching a leading independent position, basic entrepreneurial experience and will be given an opportunity to promptly commercialize her research. Moreover, the fellowship will lead to creation of several new sustainable international networks.
Original text from CORDIS.
Participants
- MEDITERANSKI INSTITUT ZA ISTRAZIVANJE ZIVOTA · SplitCoordinatorCroatia
Links
Data: CORDIS, © European Union