The goal of this project is to decipher the relationship between environmental stress and protein-based inheritance. Protein-based heritable elements, best understood in yeast and other fungi, provide a new mechanism for inheritance and memory. Traits controlled by these elements are not directly encoded in DNA sequences. Instead, they depend on the presence of an altered (typically, aggregated) protein isoform (termed a prion), which can convert a normal cellular protein of the same amino acid sequence into a prion state. This work will investigate the role of stress in protein-based inheritance. The work could have broad significance for the industrial use of yeast, for example in production of alcohol and biofuels (processes associated with severe stresses). Additional outcomes will come from integration of the research with course development, teaching, and mentoring (including students from underrepresented groups), which will contribute to education in the areas of genetics, biochemistry and biotechnology. The project will also provide support for research infrastructure by strengthening the interdisciplinary centers and groups at Georgia Institute of Technology.<br/><br/>Formation and propagation of yeast prions is modulated by other proteins (termed chaperones), that are normally involved in protein folding and defense against environmental stresses. This project investigates how stresses, such as heat shock, influence protein-based inheritance, what is the role of chaperones in these effects, and what is the impact of protein-based stress "memory" on stress resistance. The unifying hypothesis tested in this project is that prion-like aggregation could be adaptive due to generation of a subpopulation of cells, with a prion-based "memory" of stress, that are induced under stress conditions and possess increased resistance to subsequent stresses. Toxic prion aggregates may occur as by-products of such adaptive aggregation and are counteracted by the cellular stress defense machinery. Mechanisms of the effects of heat shock on prions and the role of intracellular relocation of chaperones in these effects will be investigated using a combination of genetic, cytological, biochemical and proteomic techniques.<br/><br/>This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.