Objective
Autoimmunity is caused by chronic inflammation mediated by T- and B-lymphocytes. Thus far, treatment of autoimmunity consists of general immune suppressants, causing unwarranted side effects, without curing disease. Therefore, the need for a specific treatment targeting the cause of disease is growing. In this fellowship will focus on elucidating how SNPs (single nucleotide polymorphisms) in RasGRP1 play a role in aberrant lymphocyte activity in patients with autoimmunity. RasGRP1 is critical in the activation of Ras, resulting in lymphocyte activation. Preliminary data show that a point mutation in Rasgrp1, Rasgrp1Anaef, results in autoimmunity in mice, characterized by anti-nuclear antibodies and activated CD4+ T cells. Moreover, Rasgrp1Anaef/wildtype heterozygote mice show a similar phenotype, arguing that one wildtype allele cannot compensate for the Rasgrp1Anaef allele. We have established that hypomorphic Rasgrp1 variants can exert a dominant negative effect, which relies on coiled-coil mediated dimerization with wildtype Rasgrp1. This new concept of RasGRP1 dimerization, suggests that monoallelic, non-synonymous RasGRP1 variants may affect the activity of a RasGRP1 dimer in patients.
In the proposed fellowship, I will: (1) Model non-synonymous SNPs in patients to our structure of RasGRP1 and test the functional effect, (2) Establish how dimerization affects RasGRP1 function, and (3) Establish if RasGRP1 signaling is aberrant in lymphocytes of patients.
This will help us understand how autoimmunity comes about, and will provide new potential strategies for development of more specific therapies. I anticipate that these RasGRP1-centric studies will function as a paradigm for future studies on dysregulated signaling pathways in autoimmune T cells. This fellowship will put me in an excellent position to start my independent research in Europe, introducing functional research of SNPs in key lymphocyte signaling molecules to the field of (pediatric) rheumatology.
Fields of science (EuroSciVoc)
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
- medical and health sciences clinical medicine rheumatology
- medical and health sciences basic medicine immunology autoimmune diseases
- natural sciences biological sciences genetics mutation
- natural sciences mathematics pure mathematics mathematical analysis functional analysis
- natural sciences biological sciences genetics nucleotides
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Programme(s)
Multi-annual funding programmes that define the EU’s priorities for research and innovation.
Multi-annual funding programmes that define the EU’s priorities for research and innovation.
Topic(s)
Calls for proposals are divided into topics. A topic defines a specific subject or area for which applicants can submit proposals. The description of a topic comprises its specific scope and the expected impact of the funded project.
Calls for proposals are divided into topics. A topic defines a specific subject or area for which applicants can submit proposals. The description of a topic comprises its specific scope and the expected impact of the funded project.
Call for proposal
Procedure for inviting applicants to submit project proposals, with the aim of receiving EU funding.
Procedure for inviting applicants to submit project proposals, with the aim of receiving EU funding.
FP7-PEOPLE-2012-IOF
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Funding Scheme
Funding scheme (or “Type of Action”) inside a programme with common features. It specifies: the scope of what is funded; the reimbursement rate; specific evaluation criteria to qualify for funding; and the use of simplified forms of costs like lump sums.
Funding scheme (or “Type of Action”) inside a programme with common features. It specifies: the scope of what is funded; the reimbursement rate; specific evaluation criteria to qualify for funding; and the use of simplified forms of costs like lump sums.
Coordinator
3584 CX Utrecht
Netherlands
The total costs incurred by this organisation to participate in the project, including direct and indirect costs. This amount is a subset of the overall project budget.