Center for Systems Biology of Cellular Stress Responses

描述（由申请人提供）：这是一项建立UCSD系统生物学中心以研究细胞应激反应的提案。系统生物学在功能基因组学和蛋白质组学（涉及收集和分析大量数据以识别基因组及其相互作用）以及合成生物学（涉及生物学理论的发展及其工程电路测试）领域取得了巨大进展。UCSD中心的目标是制定研究策略，通过这些策略，可以将这两种方法联系起来，以开发有关临床相关人类健康问题的数学基础见解。这将涉及在几个尺度上动态调节生物系统的计算建模和实验研究：全基因组网络，功能模块和概括调节行为本质的简化系统。对遗传毒性、致病性或代谢应激的细胞反应涉及动态调节的信号传导事件，并负责保护生物体的修复、存活或细胞周期调节中的协调步骤。然而，这种应激反应的错误调节不仅损害细胞抑制损伤的能力，而且可能导致进一步的损伤，如慢性炎性疾病和癌症所表现的。为了了解细胞应激反应，我们建议创建一个系统生物学中心，其中来自UCSD几个部门和部门的多学科实验室小组贡献了不同的专业知识和方法，从功能基因组学，蛋白质组学和网络重建到数学建模，合成生物学和动态细胞生物成像方法与新的体内报告。该中心的具体目标是：（1）通过识别调节器并模拟其在调节网络中的作用机制，了解压力反应的调节;（2）了解细胞应激反应如何影响潜伏病原体（HIV）以及如何受到其他动态控制系统的影响（如肥大细胞的昼夜节律周期）（3）理解使用自然和合成系统的动态调节和稳态控制的设计原理（4）发展一个全国性的领导者社区，通过多学科合作和共同的核心设施来应对概念、技术和教育挑战（5）提供机会，培养当今和未来的系统生物学领导者，揭示有关临床相关人类健康问题的数学基础见解。 相关性：细胞对压力（如病原体，辐射，代谢失衡或毒素）的反应对人类健康至关重要;压力反应不仅限制了损害，而且失调可能导致癌症和炎症性疾病。所提出的实验和预测建模相结合的方法有望了解调控系统，这是开发急需的疾病预防和治疗策略的关键。

DESCRIPTION (provided by applicant): 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: 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.