PXD020994

PXD020994 is an original dataset announced via ProteomeXchange.

Title	Discovery of drugs to treat cytokine storm-induced cardiac dysfunction
Description	SARS-CoV2 infection leads to cardiac injury and dysfunction in 20-30% of hospitalized patients and higher rates of mortality in patients with pre-existing cardiovascular disease. Inflammatory factors released as part of the 'cytokine storm' are thought to play a critical role in cardiac dysfunction in severe COVID-19 patients. Here we use human cardiac organoid technology combined with high sensitivity phosphoproteomics and single nuclei RNA sequencing to identify inflammatory targets inducing cardiac dysfunction. This new pipeline allowed rapid progress and identification of putative therapeutics. We identify a novel interferon-gamma driven BRD4 (bromodomain protein 4)-fibrosis/iNOS axis as a key intracellular mediator of inflammation-induced cardiac dysfunction. This axis is therapeutically targetable using BRD4 inhibitors, which promoted full recovery of function in human cardiac organoids and prevented severe inflammation and death in a cytokine-storm mouse model. The BRD inhibitor INCB054329 was the most efficacious, and is a prime candidate for drug repurposing to attenuate cardiac dysfunction and improve COVID-19 mortality in humans.
HostingRepository	PRIDE
AnnounceDate	2022-02-21
AnnouncementXML	Submission_2022-02-21_03:06:19.819.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Sean Humphrey
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	phosphorylated residue
Instrument	Q Exactive HF-X

Revision	Datetime	Status	ChangeLog Entry
0	2020-08-19 07:49:10	ID requested
⏵ 1	2022-02-21 03:06:20	announced

Mills RJ, Humphrey SJ, Fortuna PRJ, Lor M, Foster SR, Quaife-Ryan GA, Johnston RL, Dumenil T, Bishop C, Rudraraju R, Rawle DJ, Le T, Zhao W, Lee L, Mackenzie-Kludas C, Mehdiabadi NR, Halliday C, Gilham D, Fu L, Nicholls SJ, Johansson J, Sweeney M, Wong NCW, Kulikowski E, Sokolowski KA, Tse BWC, Devil, é, e L, Voges HK, Reynolds LT, Krumeich S, Mathieson E, Abu-Bonsrah D, Karavendzas K, Griffen B, Titmarsh D, Elliott DA, McMahon J, Suhrbier A, Subbarao K, Porrello ER, Smyth MJ, Engwerda CR, MacDonald KPA, Bald T, James DE, Hudson JE, BET inhibition blocks inflammation-induced cardiac dysfunction and SARS-CoV-2 infection. Cell, 184(8):2167-2182.e22(2021) [pubmed]

ProteomeXchange project tag: Sars-cov-2, Covid-19

submitter keyword: heart, cardiac organoids, cytokine storm, phosphoproteomics, EasyPhos, COVID-19, SARS-CoV2

Sean Humphrey
contact affiliation	School of Life and Environmental Sciences, Charles Perkins Centre, University of Sydney, Australia
contact email	sean.humphrey@sydney.edu.au
lab head
Sean Humphrey
contact affiliation	Sydney University
contact email	sean.humphrey@sydney.edu.au
dataset submitter

Dataset FTP location NOTE: Most web browsers have now discontinued native support for FTP access within the browser window. But you can usually install another FTP app (we recommend FileZilla) and configure your browser to launch the external application when you click on this FTP link. Or otherwise, launch an app that supports FTP (like FileZilla) and use this address: ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2022/02/PXD020994

PRIDE project URI

• PRIDE
  1. PXD020994
     1. Label: PRIDE project
     2. Name: Discovery of drugs to treat cytokine storm-induced cardiac dysfunction