A multimethod simulation paradigm for investigating complex cellular responses in biological systems of aging and disease

Abstract

Classical studies in toxicology and disease research have relied on the use of high-dose experiments and often lacked quantitative and comprehensive components essential to understanding biological queries. These shortcomings in the research community have been the result of modern methodological limitations, however, more robust and expansive experimental and computational methods are emerging. In this dissertation, I present a novel multimethod computational simulation paradigm that adds value to new and existing studies of toxicological and pathological endeavors. First, I established the use of this approach for pharmacokinetic and pharmacodynamic applications, with published examples in regulatory exposure toxicology and contemporary dose-response nuances. Following establishing the success of this approach in toxicology, I then applied this methodology to the broader question of degenerative aging, as it has been arduous with conventional techniques to understand the various mechanisms that contribute to and protect against cellular aging. The foundational simulation created for general cellular aging was then expanded in the context of tauopathies and Alzheimer's disease to better quantify and understand the pathways involved in this age-dependent disorder. The final results presented here improve experimental translatability, robustness and descriptiveness in order to better understand age-related diseases. More broadly, this dissertation in totality attempts to minimize quantitative deficits in toxicological and pharmacological research.