Quantitative Systems Biomedicine and Pharmacology for Multiscale Tissue Damage

PROJECT SUMMARY/ABSTRACT Chemical, physical, and biological processes interact across multiple length and time scales, leading to consequences for human physiology, disease progression, and medical therapeutics. The collective behaviors of these processes across multiple scales cannot be explained by studying the isolated parts at a single scale. Multiscale systems biomedicine approaches allow for quantitative descriptions of interconnected processes, which aid in understanding the mechanisms for the links between the processes that cannot be decoupled easily in experiments. The overall vision for the PI’s research program is to develop multiscale computational models and methods for building and solving those models to enhance understanding of the mechanisms governing tissue remodeling and damage as a result of diseases and infections and to simulate the treatment of those conditions to improve human health. The proposed research addresses the unmet need to compile the multiple processes that contribute to homeostatic tissue remodeling and the onset and progression of chronic tissue damage into systematic computational frameworks capable of taking the interconnected chemical, physical, and biological factors into account in a coupled fashion and in the appropriate magnitudes and sequences to make testable predictions. In the absence of such frameworks, unraveling the network of events in tissue remodeling and damage will continue to be perplexing, and the development of effective pharmaceutical treatments will likely remain piecemeal and slow. The proposed research focuses on tissue damage processes that involve changes to the extracellular matrix (ECM), which provides biochemical and structural support to surrounding cells. Building multiscale computational models for the chemical and biological processes that result in structural addition or depletion of ECM, which damages various tissues, and related immune involvement will increase fundamental mechanistic understanding of human tissues and lay the foundation for advances in disease treatment and prevention. The rationale is that multiscale computational models provide insights into the complex network of the effects of molecular-level actions of chemicals such as glucose, cytokines, hormones, and pharmaceuticals on the cellular, tissue, and whole-body levels of physiology. The goal for the next five years is to create and refine multiscale models to improve physiological understanding of tissue remodeling and damage in various human, animal, and engineered tissue microenvironments. Two key challenges related to the unmet need will be pursued: 1) relating molecular and cellular level information to macroscopic tissue and organ systems level clinically relevant phenotypes and 2) cell migration through 3D microenvironments. The goal and key challenge areas build upon the systems biomedicine methods the PI’s lab has adopted and the recent results they have produced related to multiscale computational models applied to diabetic kidney disease, lung infection and fibrosis, cancer and immune cell migration, bone remodeling, and polymer implants for drug delivery.