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PTPN22 IN T1D

Effect of PTPN22 on Treg to Teff equilibrium in human and murine autoimmune diabetes

Coordinatore	Ospedale San Raffaele Organization address address: Via Olgettina 60 city: Milano postcode: 20132 contact info Titolo: Dr. Nome: Maria Rosa Cognome: Pedrazzi Email: send email Telefono: +39 02 2643 4845 Fax: +39 02 2643 4717
Nazionalità Coordinatore	Italy [IT]
Totale costo	100˙000 €
EC contributo	100˙000 €
Programma	FP7-PEOPLE Specific programme "People" implementing the Seventh Framework Programme of the European Community for research, technological development and demonstration activities (2007 to 2013)
Code Call	FP7-PEOPLE-2010-RG
Funding Scheme	MC-IRG
Anno di inizio	2011
Periodo (anno-mese-giorno)	2011-04-01 - 2015-03-31

Partecipanti

#	participant	country	role	EC contrib. [€]
1	Ospedale San Raffaele Organization address address: Via Olgettina 60 city: Milano postcode: 20132 contact info Titolo: Dr. Nome: Maria Rosa Cognome: Pedrazzi Email: send email Telefono: +39 02 2643 4845 Fax: +39 02 2643 4717	IT (Milano)	coordinator	100˙000.00
2	FONDAZIONE CENTRO SAN RAFFAELE DEL MONTE TABOR Organization address address: Via Olgettina 60 city: MILANO postcode: 20132 contact info Titolo: Mr. Nome: Mario Cognome: Valsecchi Email: send email Telefono: +39 02 2643 2729 Fax: +39 02 26432752	IT (MILANO)	participant	100˙000.00

Mappa

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cells signaling w murine lyp equilibrium ptpn teff susceptibility pre disease pep diabetic genetic polymorphism human environmental t insulin destruction individuals diabetes treg progression selected models functional producing

Obiettivo del progetto (Objective)

'Type 1 diabetes (T1D) is a chronic inflammatory disease, where predisposing genetic factors along with environmental influences result in loss of immunological tolerance and destruction of insulin-producing beta cells. Genetic studies have identified three main T1D susceptibility loci, the human leukocyte antigens (HLA), insulin and most recently PTPN22, which encodes for Lyp/Pep, a lymphoid tyrosine phosphatase. A single nucleotide polymorphism (SNP) in PTPN22 at codon 620 leads to one amino-acid substitution, Arg to Trp (R620W), associated with an increase in T1D risk. A perturbation in the effector (Teff) to regulatory T cell (Treg) equilibrium seems to be implicated in T1D and most cases of autoimmunity. Functional analysis in individuals carrying the R620W polymorphism indicate a 'gain of function mutant' resulting in reduced TCR signaling. However, it is not currently known how PTPN22 is involved in mediating T1D susceptibility: effects on Treg and/or Teff thymic selection and peripheral homeostasis may be responsible. Understanding the mechanisms involved could be a key to our understanding of T1D pathogenesis. In addition, strategies that directly target Teff or Treg by inhibiting signaling from PTPN22 could be successful in halting T1D progression. The goal of this project is to analyze the role of PTPN22 on Treg and Teff equilibrium in (pre)diabetic human individuals and selected mouse models of T1D. The specific aims of this Marie-Curie RIG are: 1. Define the role of PTPN22 (R620W allele) on Treg and Teff cells in healthy versus (pre)diabetic individuals, and 2. Determine the role of PTPN22 signaling on Teff and/or Treg in two well-characterized murine models of T1D, (virally-induced [RIP-LCMV] and spontaneous [NOD]. Objectives to be achieved: 1. Functional characterization of PTPN22 mutation on Treg and Teff cells in (pre)diabetic human individuals. 2. Dissection of PTPN22 signaling in selected murine models of T1D crossed to Lyp/Pep deficient mice.'

Introduzione (Teaser)

Type 1 diabetes (T1D) is an autoimmune disease that is caused by the immune-mediated destruction of insulin-producing cells in the pancreas. Lifestyle, environmental and genetic factors seem to contribute to disease onset and progression.