The basic components of biological systems – genes, proteins, metabolites and other molecules – work together in a highly orchestrated manner within cells to promote normal development and sustain health. Understanding how these interconnected components of biological pathways and networks are maintained in health, and how they become perturbed by genetic and environmental stressors and cause disease, is challenging but essential to developing new and better therapies to return perturbed networks to their normal state.
To achieve this goal, the Library of Integrated Network-based Cellular Signatures (LINCS) program aims to develop a “library” of molecular signatures, based on gene expression and other cellular changes that describe the response that different types of cells elicit when exposed to various perturbing agents, including siRNAs and small bioactive molecules. High-throughput screening approaches will be used to interrogate the cells and mathematical approaches will be used to describe the molecular changes and patterns of response. The data will be collected in a standardized, integrated, and coordinated manner to promote consistency and comparison across different cell types.
The underlying premise of the LINCS program is that disrupting any one of the many steps of a given biological process will cause related changes in the molecular and cellular characteristics, behavior, and/or function of the cell – also known as the cellular phenotype. A cellular phenotype is, in turn, intended to reflect signatures derived for comparable assays of clinical states. Observing how and when a cell’s phenotype is altered by specific stressors can provide clues about the underlying mechanisms involved in perturbation and ultimately disease.
LINCS data will be made openly available as a community resource that can be easily scaled up and augmented to address a broad range of basic research questions and to facilitate the identification of biological targets for new disease therapies.
The LINCS program is being implemented in two phases.
Phase 1 began in FY 2010 and focuses on the following activities:
- Large-scale production of perturbation-induced molecular and cellular signatures
- Creation of a database, common data standards and public user interface for accessing the data
- Computational tool development and integrative data analyses
- Development of new cost-effective, molecular and cellular phenotypic assays
- Integration of existing datasets into LINCS
Pending the outcome of Phase 1, Phase 2 will begin in FY 2013 and involve one or more new research initiatives that expand the program based on what is learned from the exploratory initiatives of FY10–12.
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