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Testing the therapeutic potential of class 3 semaphorins to restore tissue homeostasis in inflammatory arthritis

Tuesday 7 April 2015

Testing the therapeutic potential of class 3 semaphorins to restore tissue homeostasis in inflammatory arthritis

Dr. Samuel García Pérez / Dr. Kris Reedquist/ Prof. Tim Radstake

In rheumatoid arthritis (RA) and other forms of inflammatory arthritis, chronic inflammation of synovial tissue causes irreversible joint disability, leading to loss of quality of life and significant socio-economic costs. Improper recruitment, survival and retention of white blood cells (such as macrophages, lymphocytes and neutrophils) to the synovial tissue, enhanced synovial vascularization, and hyperplasia of stromal fibroblast-like synoviocytes (FLS) perpetuate inflammation, eventually leading to cartilage destruction and bone erosion populations. Together, these events lead to the erosion of bone and cartilage destruction. Novel therapeutic strategies which interfere with these processes may therefore be beneficial in improving treatment of patients with inflammatory arthritis.

Semaphorins comprise a large family of cell surface and secreted proteins that play an important role in cell movement and guidance, best known for their roles in embryology,neuronal development, and angiogenesis. They exert their effects by binding to counter-receptors, plexins, neutropilins and other proteins on other cells. Increasing evidence suggests that semaphorins are not only involved in tumor growth and metastasis, but also regulate immune cell recruitment, activation and survival, processes relevant to inflammatory arthritis. A small number of studies have indicated that some semaphorins and their receptors may be differentially expressed in RA and osteoarthritis (OA) synovial tissue, but nothing is known about the potential role of semaphorins in inflammatory arthritis. Based on the available literature, and preliminary studies from our laboratory, we propose that expression of semaphorins, in particular class 3 semaphorins, serves to maintain tissue homeostasis. Alterations in the expression of these proteins contribute to immune cell influx and retention, enhanced vascularization, and the hyperplasive, invasive properties of FLS in inflammatory arthritis. Therefore, restoration of expression or administration of exogenous class 3 semaphorins could represent a novel therapeutic strategy.

Objectives to be reached during the internship
Step1: Determine the expression, cellular distribution and regulation of class 3 semaphorins in synovial tissue and relevant cell populations.

Expression of class 3 semaphorins in FLS and monocytes/macrophages
Effect of FLS and monocytes/macrophages stimulation on semaphoring expression

Step2: Determine the functional consequences of semaphorin ligation

Effect of class 3 semaphorins on FLS migration and invasion
Effect of class 3 semaphorins on macrophage viability
Determine the molecular pathways involved

During the internship, the student will be directly supervised from the scientific point of view by Dr. García Pérez (post-doc in Prof. Radstake group) and by Dr. Kris Reedquist (Assistant Professor Utrech University) and on the lab-practice Dr. García Pérez. The student will take advantage by a young and enthusiast group focusing on discovery of new therapeutic target in autoimmune diseases, with a long-standing technical and clinical expertise.
The project involves the implementation of molecular and cell biology techniques and traditional statistical approaches. The maximal accuracy and commitment to the project are therefore required and only highly motivated students will be considered.

Techniques: Culture of FLS, monocyte isolation and macrophage differentiation, isolation of RNA, invasion and migration assays, viability assays, RT-qPCR.

Duration: 6 or 9 months

Contact: Dr. Samuel García Pérez, S.GarciaPerez@umcutrecht.nl