Project ID NS-MH2023_01


Co Supervisor 1A IoPPN/Wolfson CARDWebsite

Co Supervisor 1B IoPPN/Wolfson CARDWebsite

Additional Supervisor Mathilde "Tilly" Israel

Neuroimmune mechanisms of inflammatory bowel syndrome (IBS)

Fibromyalgia is an incurable condition characterized by chronic widespread pain, fatigue, and emotional distress. Despite that >2% (mostly women) of the population live with fibromyalgia, there are no effective therapies. The mechanisms responsible remained unknown until our transformational discovery that fibromyalgia is caused by autoantibodies, and that patient symptoms can be transferred to mice by administration of patient antibodies (IgG).

A third of fibromyalgia patients also suffer from the unexplained condition inflammatory bowel syndrome (IBS). IBS is common (>10%) and regularly has a severe impact on quality of life. This studentship offers an opportunity to examine whether autoantibodies are responsible for IBS and other chronic visceral pains.

Aim 1: Collate patient data with regards to diagnosis, symptoms, and co-morbidities. Purify IgG from collected sera.

Aim 2. Evaluate behavioural changes and bowel function in vivo in mice.

2.1 Assess stool frequency and bowel motility before and after intraperitoneal administration of IgG from patients and healthy subjects.

2.2 Assess spontaneous murine behaviours (social isolation, rearing and writhing) before and after IgG using a Home Cage AnalyzerTM.

Aim 3. Investigate hypersensitivity of extrinsic sensory neurons innervating the colon in IgG-treated mice as a cause of pain and dysfunction.

3.1 Assess excitability in gut-nerve preparations from mice treated with patient IgG using ex vivo electrophysiology.

In parallel, immunohistochemistry, in situ hybridization and transcriptomic analysis will identify cells and molecules involved. The student will present findings at national and international meetings and to patients. Year 4 will be focused on writing manuscripts, thesis, and applications.

Representative Publications

A. Goebel, E. Krock, C. Gentry, M. R. Israel, A. Jurczak, C. M. Urbina, K. Sandor, N. Vastani, M. Maurer, U. Cuhadar, S. Sensi, Y. Nomura, J. Menezes, A. Baharpoor, L. Brieskorn, A. Sandström, J. Tour, D. Kadetoff, L. Haglund, E. Kosek, S. Bevan, C. I. Svensson, D. A. Andersson, Passive transfer of fibromyalgia symptoms from patients to mice. J. Clin. Invest. 131, 144201 (2021). (This paper demonstrates that the previously unexplained syndrome fibromyalgia is an autoantibody mediated condition.)

Quallo T, Vastani N, Horridge E, Gentry C, Parra A, Moss S, Viana F, Belmonte C, Andersson DA, Bevan S (2015) TRPM8 is a neuronal osmosensor that regulates eye blinking in mice. Nat Commun 6:7150.(Discovery of TRPM8 as an exquisitely sensitive sensor of osmolality that controls the rate of eye blinking.)

Israel, M.R., Tanaka, B.S., Castro, J., Thongyoo, P., Robinson, S.D., Zhao, P., Deuis, J.R., Craik, D.J., Durek, T., Brierley, S.M., Waxman, S.G., Dib‐Hajj, S.D. and Vetter, I. (2019), NaV1.6 regulates excitability of mechanosensitive sensory neurons. J Physiol, 597: 3751-3768. doi:10.1113/JP278148