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

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."

Field of science

  • /medical and health sciences/basic medicine/physiology/homeostasis
  • /natural sciences/biological sciences/genetics and heredity/mutation
  • /medical and health sciences/clinical medicine/endocrinology/diabetes
  • /natural sciences/biological sciences/genetics and heredity/nucleotide

Call for proposal

FP7-PEOPLE-2010-RG
See other projects for this call

Funding Scheme

MC-IRG - International Re-integration Grants (IRG)

Coordinator

OSPEDALE SAN RAFFAELE SRL
Address
Via Olgettina 60
20132 Milano
Italy
Activity type
Private for-profit entities (excluding Higher or Secondary Education Establishments)
EU contribution
€ 100 000
Administrative Contact
Maria Rosa Pedrazzi (Dr.)

Participants (1)

FONDAZIONE CENTRO SAN RAFFAELE DEL MONTE TABOR

Participation ended

Italy
EU contribution
€ 100 000
Address
Via Olgettina 60
20132 Milano
Activity type
Research Organisations
Administrative Contact
Mario Valsecchi (Mr.)