In this project we aim to create a first installment of data generation and analysis for the LINCS program. Specifically, we will use a novel approach to genome-wide expression profiling developed at the Broad Institute (based on a Luminex bead assay) to catalog the cellular consequences of diverse small-molecule and genetic perturbations in a breadth of human cell lines. We will perform these perturbations in 20 cell types chosen for their biological diversity and interest to the broad scientific community. For the genetic perturbations, we will profile the cellular consequences of treatment of each of these cell lines with 4,000 small-molecule compounds of interest to the community (including compounds emerging from the MLPCN network). For the genetic perturbations, we will perform both gain- and loss-of-function studies for 3,000 human genes. The resulting expression data will be made publicly available without restriction, and importantly, will be accompanied by a series of analytical tools that will enable researchers to query the data via a web interface. The project has been configured so that it a) can scale to larger efforts in the future, b) can accommodate technology platform changes in the future, and c) can accommodate the integration with other types of data.
The proposed project is expected to enable the biomedical research community to interact with a rich database of functional perturbational data that can support a) the discovery of function of unknown components of the genome, b) the annotation of function of small molecules, and c) the linking of disease sates with small-molecule or genetic perturbational signatures, thereby providing insight into the biological basis of disease and perhaps even initial insights into new therapeutic opportunities.
|Niepel, Mario; Hafner, Marc; Duan, Qiaonan et al. (2017) Common and cell-type specific responses to anti-cancer drugs revealed by high throughput transcript profiling. Nat Commun 8:1186|
|Corsello, Steven M; Bittker, Joshua A; Liu, Zihan et al. (2017) The Drug Repurposing Hub: a next-generation drug library and information resource. Nat Med 23:405-408|
|Zhu, Xiaodong; Girardo, David; Govek, Eve-Ellen et al. (2016) Role of Tet1/3 Genes and Chromatin Remodeling Genes in Cerebellar Circuit Formation. Neuron 89:100-12|
|Pikman, Yana; Puissant, Alexandre; Alexe, Gabriela et al. (2016) Targeting MTHFD2 in acute myeloid leukemia. J Exp Med 213:1285-306|
|Wilson, Frederick H; Johannessen, Cory M; Piccioni, Federica et al. (2015) A functional landscape of resistance to ALK inhibition in lung cancer. Cancer Cell 27:397-408|
|Olson, David E; Udeshi, Namrata D; Wolfson, Noah A et al. (2014) An unbiased approach to identify endogenous substrates of ""histone"" deacetylase 8. ACS Chem Biol 9:2210-6|
|Vempati, Uma D; Chung, Caty; Mader, Chris et al. (2014) Metadata Standard and Data Exchange Specifications to Describe, Model, and Integrate Complex and Diverse High-Throughput Screening Data from the Library of Integrated Network-based Cellular Signatures (LINCS). J Biomol Screen 19:803-16|
|Duan, Qiaonan; Flynn, Corey; Niepel, Mario et al. (2014) LINCS Canvas Browser: interactive web app to query, browse and interrogate LINCS L1000 gene expression signatures. Nucleic Acids Res 42:W449-60|
|Wawer, Mathias J; Li, Kejie; Gustafsdottir, Sigrun M et al. (2014) Toward performance-diverse small-molecule libraries for cell-based phenotypic screening using multiplexed high-dimensional profiling. Proc Natl Acad Sci U S A 111:10911-6|
|Sharifnia, Tanaz; Rusu, Victor; Piccioni, Federica et al. (2014) Genetic modifiers of EGFR dependence in non-small cell lung cancer. Proc Natl Acad Sci U S A 111:18661-6|
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