PXD025998

PXD025998 is an original dataset announced via ProteomeXchange.

Title	Alagebrium chloride therapy acts to preserve beta cell health
Description	Aims/hypothesis AGEs are considered environmental contributors of type 1 diabetes, but the exact role AGEs play early in pathogenesis of the disease, remains unidentified. We aimed to reduce AGEs with the pharmacotherapy alagebrium chloride in MIN6N8 cells and early in life in NOD mice to determine its impact on beta cell immunogenicity, function, and disease progression. Methods MIN6N8 cells were cultured with AGEs with or without short-term alagebrium therapy to determine the effect on ER stress and beta cell antigen presentation via a reporter assay for protein responses in the unfolded protein response, the enzymatic activity of endoplasmic reticulum aminopeptidase-1 (ERAP1) and the immunopeptidome. To determine the effect of short-term alagebrium therapy on beta cells in vivo, female NOD mice were treated with alagebrium and insulin secretion, insulitis, and immune cell repertoire were studied. Adoptive transfer studies and diabetes progression studies were used to consider the impact of alagebrium on immune cell function and disease outcome. Results In MIN6N8 cells, alagebrium therapy inhibited the induction of endoplasmic reticulum (ER) stress and the activity of ERAP1 by AGE-modified proteins. Alagebrium treated-MIN6N8 cells did not change the MHC Class I presentation of known beta cell antigens but did induce proteomic changes related to ER homeostatic pathways. Prior to overt autoimmune diabetes, female NOD mice treated with alagebrium for 30-40 days had improved insulin secretion, reduced insulitis and amplified proportions of pancreatic CD8+ T cells, mature B cells and F4/80+ macrophages. Splenocytes from alagebrium-treated mice adoptively transferred disease to NODscid recipients and maintained interferon production in vitro. While partial protection of islets by alagebrium was seen following the adoptive transfer of activated NOD G9C8 transgenic TCR CD8+ T cells, alagebrium therapy in NOD mice did not reduce diabetes progression. Conclusions/interpretation Our data suggests that in experimental models of diabetes, short-term alagebrium treatment allows for beta cell improvement, and maintenance of immune cell function, which does not fully mitigate diabetes progression.
HostingRepository	PRIDE
AnnounceDate	2021-06-29
AnnouncementXML	Submission_2021-06-28_21:19:39.965.xml
DigitalObjectIdentifier	https://dx.doi.org/10.6019/PXD025998
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Supported dataset by repository
PrimarySubmitter	Pouya Faridi
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: 10090;
ModificationList	monohydroxylated residue; iodoacetamide derivatized residue
Instrument	TripleTOF 5600; Orbitrap Fusion

Revision	Datetime	Status	ChangeLog Entry
0	2021-05-13 03:30:25	ID requested
⏵ 1	2021-06-28 21:19:40	announced

Dataset with its publication pending

submitter keyword: Diabetes HLA proteomics

Anthony Purcell
contact affiliation	Deputy Head (Research), Department of Biochemistry and Molecular Biology Head Immunoproteomics Laboratory Infection and Immunity Program Room 214, level 2, 15 Innovation Walk Monash Biomedicine Discovery Institute Monash University, Clayton Campus Clayton 3800 Victoria Australia
contact email	anthony.purcell@monash.edu
lab head
Pouya Faridi
contact affiliation	Monash University
contact email	pouya.faridi@monash.edu
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD025998
     1. Label: PRIDE project
     2. Name: Alagebrium chloride therapy acts to preserve beta cell health