Asymmetric cell division (ACD) is a fundamental mechanism by which cells of a single genetic makeup divide and generate cells of distinct phenotypes and fates. Although ACD has been well studied in the context of organismal development and stem cell self-renewal, an emerging function of ACD is asymmetric partitioning of aging determinants to produce progeny cells with contrasting vitality and proliferative potential. This process is thought to enable rejuvenation from accumulated damages and maintenance of high fitness of a rapidly dividing cell population. This research project proposes to use the unicellular eukaryote, the budding yeast Saccharomyces cerevisiae, as the experimental model to understand how different types of aging determinants are partitioned asymmetrically during each mitotic cell division. Budding yeast cells undergo highly stereotypic ACD to give rise to a newborn-like daughter cell and a mother cell with more advanced aging characteristics such as reduced replicative potential and viability. We will build upon exciting recent findings to pursue four specific aims. The first two aims investigate how two major organelles, ER and mitochondria, facilitate the asymmetric retention of proteome damage during ACD.
The third aim examines the mechanism by which ACD partitions aged vs newly synthesized cellular components between the mother and the bud and the impact of this process on aging asymmetry, while the fourth uses mathematical modeling to investigate the impact of asymmetric segregation on cellular replicative aging and population fitness. As aging is a driving force behind many devastating human diseases, from Alzheimer's to cancer, and recent studies have provided evidence for asymmetric segregation of aging factors in stem cells, the principles and mechanisms explored in our study are likely to provide fundamental insights facilitating basic and translational research on human health and regenerative medicine.
The proposed project is relevant to public health because its goal is to understand how cells age as they divide and proliferate. It is well known that cellular aging is a driving force behind many devastating human diseases, such as Alzheimer's disease, Parkinson's disease, and cancer, but it remains unclear what molecular determinants cause cells to age and how these determinants are managed in order to maintain a healthy proliferative potential for the population. Our study is designed to use the single cellular eukaryotic model, yeast, to decipher the most intrinsic mechanisms of cellular aging. We will strive to understand how damaged proteins are managed and propagated during each cell division, and how new and aged components of the cell are separated when the cell divides to produce a young cell and an aged cell. We will also build mathematical models based on our experimental observations in order to understand cellular aging on a theoretical and quantitative level. The basic knowledge gained through our study should have broad impact on the research on human health, aging and regenerative medicine.
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