PXD030678

PXD030678 is an original dataset announced via ProteomeXchange.

Title	A druggable signaling hub of choroid plexus immune-secretory function
Description	The choroid plexus (ChP) secretes a half-liter of cerebrospinal fluid (CSF) per day into the cerebral ventricular system and gates immune cell entry into the brain as the blood-CSF barrier. Acquired hydrocephalus, characterized by ventriculomegaly from CSF accumulation, is caused by both brain infection or hemorrhage and is treated by neurosurgical CSF diversion with attendant morbidity and long-term disability. We interrogated novel rat models of post-infectious (PIH) and post-hemorrhagic hydrocephalus (PHH) using a multi-omics, systems biology platform to elucidate mechanisms of disease. Integrated analysis of new genome-level transcriptomic and proteomic ChP datasets demonstrated that lipopolysaccharide in PIH, and blood breakdown products in PHH, trigger highly similar toll-like receptor-4 (TLR4)-dependent immune responses at the ChP-CSF interface. This includes the production of a CSF “cytokine storm” elicited from activated peripherally-derived and border-associated macrophages that accumulate at the ChP. Pro-inflammatory CSF signals stimulate their cognate receptors on ChP epithelial cells in paracrine manner to acutely increase CSF secretion rate via the TNF receptor associated SPAK kinase, which binds and activates a multi-ion transporter and channel complex at the ChP apical membrane. Genetic and pharmacological immunosuppression with repurposed drugs antagonizes SPAK-dependent CSF hypersecretion and prevents acute PIH and PHH. These data expand our understanding of ChP immune-epithelial cell crosstalk, reframe PIH and PHH as related inflammatory disorders vulnerable to systemic immunomodulation, and identify a druggable hub of ChP immune-secretory function that holds promise for other neurological disorders.
HostingRepository	PRIDE
AnnounceDate	2023-11-14
AnnouncementXML	Submission_2023-11-14_08:55:05.343.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Mohammad Shahid Mansuri
SpeciesList	scientific name: Rattus norvegicus (Rat); NCBI TaxID: 10116;
ModificationList	phosphorylated residue; acetylated residue; iodoacetamide derivatized residue
Instrument	Orbitrap Fusion Lumos

Revision	Datetime	Status	ChangeLog Entry
0	2021-12-31 02:04:10	ID requested
1	2023-02-19 18:07:36	announced
⏵ 2	2023-11-14 08:55:05	announced	2023-11-14: Updated project metadata.

Dataset with its publication pending

submitter keyword: Hydrocephalus,CSF, Multi-omics, Choroide Plexus

Kristopher T. Kahle
contact affiliation	1Department of Neurosurgery, Yale School of Medicine, New Haven, CT, USA. Department of Neurosurgery, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA
contact email	kahle.kristopher@mgh.harvard.edu
lab head
Mohammad Shahid Mansuri
contact affiliation	Associate Research scientist
contact email	mohammad.mansuri@yale.edu
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/2023/02/PXD030678

PRIDE project URI

• PRIDE
  1. PXD030678
     1. Label: PRIDE project
     2. Name: A druggable signaling hub of choroid plexus immune-secretory function