This is a proposal to establish the UCSD Center for Systems Biology to study Cellular Stress Responses. Systems Biology has made huge advances in the areas of functional genomics and proteomics (that involve the collection and analysis of large amounts of data that identify gene sets and their interactions), and in the area of Synthetic Biology (that involve the development of biological theory and its testing with engineered circuits). The UCSD Centers goal is to develop research strategies by which the two approaches can be linked to develop mathematically grounded insights about clinically relevant human health problems. This will involve computational modeling and experimental studies of dynamically regulated biological systems at several scales: genome-wide networks, functional modules, and reduced systems that recapitulate the essence of the regulated behavior. Cellular Responses to genotoxic, pathogenic, or metabolic stresses involve signaling events that are dynamically regulated and are responsible for coordinated steps in repair, survival, or cell cycle regulation that protect the organism. However, misregulation of such stress responses do not only impair the cell's ability to contain the damage, but may cause further damage as manifested in chronic inflammatory diseases and cancer. In order to understand cellular stress responses, we propose to create a Center for Systems Biology in which a multi-disciplinary group of laboratories from several departments and divisions at UCSD contribute diverse expertise and approaches, ranging from functional genomics, proteomics and network reconstruction to mathematical modeling, synthetic biology and dynamic cell biological imaging approaches with novel in vivo reporters. The specific aims of the Center are to (1) understand the regulation of stress responses by identifying regulators and modeling their mechanism of action in regulatory networks; (2) understand how cellular stress responses affect latent pathogens (HIV) and are affected by other dynamic control systems (such as the circadian cycle in mast cells) (3) understand the design principles of dynamical regulation and homeostatic control using natural and synthetic systems (4) develop a national community of leaders to meet conceptual, technological and educational challenges through multi-disciplinary collaboration and common core facilities (5) provide opportunities to train today's and tomorrow's leaders in a Systems Biology that reveals mathematically grounded insights about clinically relevant human health problems.

RELEVANCE (See instructions): Cellular responses to stress (such as pathogens, irradiation, metabolic imbalances or toxins) are critical for human health; stress responses not only limit damage but misregulation can cause cancer and inflammatory diseases. The proposed combined experimental and predictive modeling approaches promise to understand the regulatory systems, which is key to the development of much needed disease-preventative and therapeutic strategies.