The advent of a wide variety of high throughput techniques has enabled the rapid sequencing of DNA and RNA and the identification of large numbers of proteins in protein complexes. These technologies, and their further iterations, have in turn allowed researchers to identify and catalog the somatic mutations in cancer, associate genetic variants with disease, the abundance of individual mRNA transcripts in every cell, the nature and expression of a range of non-coding RNA species, and the nature of modifications on histones and DNA. While the data arising from these methods has the power to produce enormous insights into cancer, the datasets produced are large, unwieldy, and of varying quality. Consequently, the role of bioinformatics in cancer research has become a necessity for the proper interpretation of data. The goal of Core B is to provide support for program investigators in the analysis and interpretation of these large datasets. It takes advantage of the expertise of Dr. Levine, a pioneer in the p53 field who has used computational approaches to reveal new insights into the p53 network, and the infrastructure at the Institute for Advanced Study. In the current iteration of the grant, the four projects will interact with Core B to continue to explore the roles and regulation of p53, with an emphasis on the context dependent nature of p53 action and the action of p53 mutants, the role of p53 in DNA damage and oncogene responses, the impact of a novel form of cell death ? ferroptosis ? on the output of the p53 network, and on developing therapeutic strategies to exploit p53 mutations or the consequences of p53 loss. All of these significant questions rely a variety of `omics technologies for assessing gene expression, chromatin configurations, and many other applications. As such, core B is essential for the proper analysis of these data and as such is central to the program's success.
CORE B NARRATIVE Cancer is the second leading cause of death in Americans and more than 50% of cancers have p53 mutations. This program project analyzes the action of p53 and its mutations in cell culture, animal models, and human tumor tissue using a variety of high throughput approaches. Core B will assist program investigators in analyzing the large datasets that accompany these analyses and use its vast expertise in p53 biology to collaborate with program investigators to develop new hypotheses based on these analyses.
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| Liu, Hengrui; Schreiber, Stuart L; Stockwell, Brent R (2018) Targeting Dependency on the GPX4 Lipid Peroxide Repair Pathway for Cancer Therapy. Biochemistry 57:2059-2060 |
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