My lab aims to define the principles and regulation of meiotic differentiation. This process, also known as gametogenesis, is a conserved developmental program that ultimately creates life for the next generation by forming reproductive cells called gametes. Because gametogenesis contains endogenous pathways that prevent age-associated damage from being passed onto progeny, mechanistic dissection of this program offers unique insights into the biology of aging as well as potential therapeutic avenues to combat age-associated diseases including cancer and neurodegeneration. Accordingly, a fundamental question emerges as to how the fitness of gametes is ensured during their production such that they contain the appropriate nuclear and cytoplasmic content to make healthy progeny. Using budding yeast Saccharomyces cerevisiae as a primary model system, we address this question in two complementary frameworks: First, in the context of gene regulation, with the aim of understanding how the essential meiotic processes that ultimately drive cellular rejuvenation are controlled by the meiotic transcriptional program. Second, we study meiotic differentiation in the context of aging, with the aim of understanding how gamete formation promotes cellular rejuvenation and how meiotic cells ensure that age-associated damage, such as protein aggregates and dysfunctional organelles, is prevented from being transmitted to subsequent progeny. We further extend our studies to multicellular and human cell line systems with an eye on the therapeutic potential of our findings.
As an Innovation Fund investigator, Elçin Ünal, Ph.D., is teaming with Gloria A. Brar, Ph.D., to investigate the stress response pathways in regulating cellular longevity. Gametogenesis, the developmental program that creates reproductive cells, can naturally reset the aging clock, culminating in progeny devoid of pre-existing age-damaged materials. However, the specific critical factors that are eliminated during the rejuvenation process and the mechanism by which this occurs are largely unknown. A similarly intriguing and enigmatic phenomenon in the aging field is hormesis, which involves mild stress-induced stimulation of protective mechanisms leading to beneficial effects including longevity. With spark funding, the Brar and Ünal team will begin to test the hypothesis that gametogenesis is a physiological manifestation of hormesis. The Ünal lab has pioneered robust cellular imaging and molecular genetic tools to study gametogenesis in the context of aging in budding yeast and has uncovered the role of the meiotic Ndt80 transcription factor in driving rejuvenation. The Brar lab has discovered that several stress pathways are transiently and moderately activated during gametogenesis in yeast. Interestingly, a subset of these pathways is activated in response to Ndt80, and thus is a strong candidate for driving cellular rejuvenation. The pair will now combine expertise in molecular genetics, genomics, cell biology, and global gene analysis to further understand the activation of stress pathways during rejuvenation. To determine how stress pathways can control the resetting of age in a cell, they will modulate the activation of key stress pathways in adult yeast cells and identify their downstream targets. This work is central to building a foundation for understanding how cellular quality control pathways influence cell age and could point to new mechanisms for reversing cellular damage to promote longevity.