Major Areas of Research
- Analysis of the signaling pathway interactions in immune cells that define context-specific responses to pathogens
- Profiling and modeling of the cellular response to complex stimuli
- Application of RNAi screening technology to the identification of signaling network components in immune cells
- Design and implementation of high-throughput and high-content assays to facilitate computational modeling of immune cell behavior and function
The Signaling Systems Unit is focused on the design, implementation, and interpretation of screening efforts to identify and determine the interactions among the components in immune cell signaling networks. We seek to determine the signal integration mechanisms that dictate the response of immune cells to combined pathogenic stimuli in a complex environment.
Recent studies of how macrophages respond to combinations of stimuli suggest that signaling networks are not irreducibly complex and that there is an infrastructure in place that dictates the frequency of signaling pathway interaction. However, cellular responses are not predictable from knowledge of single stimulus response profiles, and there is a pressing need in the biomedical research community to adopt more quantitative computational approaches to gain insight into complex biological phenomena.
We use high-throughput genetic screening to identify key cellular network components and a combination of cell biology, biochemistry, and molecular biology to characterize their function. In collaboration with other LSB groups, we seek to use complementary datasets to develop models describing the cellular response to complex stimuli and to gain insight to emergent cellular behaviors that are not predictable from knowledge of single-input responses.
Ongoing projects in the lab include the following:
- Genome-wide RNAi and chemical screens to characterize signaling network topology in hematopoietic cells and to identify the "parts list" of cellular components involved in immune cell responses
- Development of multiplex cell-based assays for screening applications and parameterization of computational models
- Assays focus on post-translational modification of signaling proteins, cellular re-localization of pathway components, and transcriptional responses to pathogenic stimuli.
- Use of the above methods to characterize the response of immune cells to increasingly complex stimuli, such as single and combined pathogenic ligands, and intact pathogens, such as bacteria and viruses
To inquire about current openings in the lab, email email@example.com.
Dr. Fraser received his B.S. in biochemistry from Heriot-Watt University, Edinburgh, Scotland, in 1990 and his Ph.D. in biochemistry from Imperial College, University of London, in 1995. He was a Wellcome Trust International postdoctoral fellow at the Vollum Institute in Portland, Oregon, from 1996 to 1999. He joined the Alliance for Cellular Signaling (AfCS) research consortium in 2000 as lead scientist of the molecular biology group at the California Institute of Technology and became co-director of the AfCS Molecular Biology Laboratory in 2005. He joined NIAID in 2008 as leader of the PSIIM Molecular and Cell Biology Team, which became the LSB Signaling Systems Unit in 2011.
His research has focused on the mechanistic basis of cellular signaling, both in G protein signaling networks and more recently in Toll-like receptor signaling in innate immune cells. He is interested in the application of systems biology approaches to decipher how mammalian cells integrate stimuli in a complex environment to ensure context-dependent cellular responses. This is vital to understanding how a breakdown in information processing through cell-surface receptors and their linked signal transduction pathways leads to human disease. Dr. Fraser has developed sophisticated approaches for RNAi-based perturbation analysis of immune cell signaling, as well as cloning platforms and plasmid repositories for high-throughput imaging and cell biological applications.
Dutta B, Azhir A, Merino LH, Guo Y, Revanur S, Madhamshettiwar PB, Germain RN, Smith JA, Simpson KJ, Martin SE, Beuhler E, Fraser ID. An interactive web-based application for comprehensive analysis of RNAi-screen data. Nat Commun. 2016 Feb 23;7:10578.
Sun J, Li N, Oh KS, Dutta B, Vayttaden SJ, Lin B, Ebert TS, De Nardo D, Davis J, Bagirzadeh R, Lounsbury NW, Pasare C, Latz E, Hornung V, Fraser ID. Comprehensive RNAi-based screening of human and mouse TLR pathways identifies species-specific preferences in signaling protein use. Sci Signal. 2016 Jan 5;9(409):ra3.
Li N, Sun J, Benet ZL, Wang Z, Al-Khodor S, John SP, Lin B, Sung MH, Fraser ID. Development of a cell system for siRNA screening of pathogen responses in human and mouse macrophages. Sci Rep. 2015 Apr 1;5:9559.
Sung MH, Li N, Lao Q, Gottschalk RA, Hager GL, Fraser ID. Switching of the relative dominance between feedback mechanisms in lipopolysaccharide-induced NF-κB signaling. Sci Signal. 2014 Jan 14;7(308):ra6.
Al-Khodor S, Marshall-Batty K, Nair V, Ding L, Greenberg DE, Fraser ID. Burkholderia cenocepacia J2315 escapes to the cytosol and actively subverts autophagy in human macrophages.Cell Microbiol. 2013 Oct 11. Epub ahead of print.
Germain RN, Meier-Schellersheim M, Nita-Lazar A, Fraser ID. Systems biology in immunology: a computational modeling perspective. Annu Rev Immunol. 2011 Apr 23;29:527-85.
Wall EA, Zavzavadjian JR, Chang MS, Randhawa B, Zhu X, Hsueh RC, Liu J, Driver A, Bao XR, Sternweis PC, Simon MI, Fraser ID. Suppression of LPS-induced TNF-alpha production in macrophages by cAMP is mediated by PKA-AKAP95-p105. Sci Signal. 2009 Jun 16;2(75):ra28.