Library of Integrated Network-Based Cellular Signatures

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.

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.

To achieve this goal, the Library of Integrated Network-based Cellular Signatures (LINCS) program is developing a “library” of molecular signatures, based on gene expression and other cellular changes that describe the response different types of cells elicit when exposed to various perturbing agents, including small bioactive molecules. High-throughput screening approaches are used to interrogate the cells and mathematical approaches are used to describe the molecular changes and patterns of response.

LINCS data are openly available as a community resource for researchers to address a broad range of basic research questions and to facilitate the identification of biological targets for new disease therapies.

The LINCS program was implemented in two parts.

The pilot phase took place from FYs 2010-2013 and focused on the following activities:

• Large-scale production of perturbation-induced molecular and cellular signatures.
• Creation of a database, common data standards, and a 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.

The current phase of the program began in FY 2014 and builds on what was learned from the pilot. This phase of the program consists primarily of LINCS Data and Signature Generation Centers. The Centers carry out the following activities:

• Generating public datasets of cellular signatures collected in response to treatment with perturbing agents.
• Developing tools to optimize the accessibility and utility of their data.
• Organizing outreach activities with the broader research community so they can make use of LINCS data and tools.

The current phase of the LINCS program also works in synergy with the NIH Big Data to Knowledge (BD2K) program through a BD2K-LINCS-Perturbation Data Coordination and Integration Center (DCIC) at the Icahn School of Medicine at Mount Sinai. Read a description of the DCIC project on the NIH Common Fund's BD2K Funded Research page.