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.

Public Health 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.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Specialized Center (P50)
Project #
5P50GM085764-03
Application #
8332812
Study Section
Special Emphasis Panel (ZGM1-CBCB-2 (SB))
Program Officer
Dunsmore, Sarah
Project Start
2010-09-18
Project End
2015-08-31
Budget Start
2012-09-01
Budget End
2013-08-31
Support Year
3
Fiscal Year
2012
Total Cost
$2,956,419
Indirect Cost
$881,853
Name
University of California San Diego
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Antonova-Koch, Yevgeniya; Meister, Stephan; Abraham, Matthew et al. (2018) Open-source discovery of chemical leads for next-generation chemoprotective antimalarials. Science 362:
Zarrinpar, Amir; Chaix, Amandine; Xu, Zhenjiang Z et al. (2018) Antibiotic-induced microbiome depletion alters metabolic homeostasis by affecting gut signaling and colonic metabolism. Nat Commun 9:2872
Cowell, Annie N; Istvan, Eva S; Lukens, Amanda K et al. (2018) Mapping the malaria parasite druggable genome by using in vitro evolution and chemogenomics. Science 359:191-199
Hoeksema, Marten A; Glass, Christopher K (2018) Nature and nurture of tissue-specific macrophage phenotypes. Atherosclerosis :
Preissl, Sebastian; Fang, Rongxin; Huang, Hui et al. (2018) Single-nucleus analysis of accessible chromatin in developing mouse forebrain reveals cell-type-specific transcriptional regulation. Nat Neurosci 21:432-439
Cowell, Annie N; Valdivia, Hugo O; Bishop, Danett K et al. (2018) Exploration of Plasmodium vivax transmission dynamics and recurrent infections in the Peruvian Amazon using whole genome sequencing. Genome Med 10:52
Link, Verena M; Duttke, Sascha H; Chun, Hyun B et al. (2018) Analysis of Genetically Diverse Macrophages Reveals Local and Domain-wide Mechanisms that Control Transcription Factor Binding and Function. Cell 173:1796-1809.e17
Zhang, Wei; Ma, Jianzhu; Ideker, Trey (2018) Classifying tumors by supervised network propagation. Bioinformatics 34:i484-i493
Xiong, Liyang; Cooper, Robert; Tsimring, Lev S (2018) Coexistence and Pattern Formation in Bacterial Mixtures with Contact-Dependent Killing. Biophys J 114:1741-1750
Cooper, Robert; Tsimring, Lev; Hasty, Jeff (2018) Microfluidics-Based Analysis of Contact-dependent Bacterial Interactions. Bio Protoc 8:

Showing the most recent 10 out of 207 publications