Early Stage Researcher 7 – Anutosh Roy

Individual Research Project 7
Project Title: Mechanisms of spinal neuroinflammation and hyperexcitability in models of joint inflammation
Supervisor: Prof. H-Georg Schaible (UKJ)
Co-supervisor(s): Dr. A. Ebersberger (UKJ) and Dr. E. Sher (Eli Lilly)

Spinal hyperexcitability is a hallmark of many chronic pain states. Communication between glial cells, immune mediators and neurons plays an important role in generation and maintenance of spinal hyperexcitability. Whilst the significance of such interactions between different cell types is evident, the underlying mechanisms are poorly understood. Fundamental open questions are: i) which cytokines are important for generation and maintenance of hyperexcitability; ii) do individual cytokines act independently or do they act as a functional network in which specific interactions take place; and iii) are there critical time windows for the action of different cytokines. These questions are substantiated by distinct observations. Firstly, the effects of spinally applied TNF-α or IL-6 are not additive, rather our evidence indicates a role for IL-6 signaling acting downstream of TNF-α suggesting a hierarchical order in the cytokine network. Secondly, neutralization of spinal TNF-α by etanercept and IL-6 by soluble gp130 inhibits spinal hyperexcitability only in defined time windows after induction of inflammation.

ESR 7 will:

1. Perform in vivo electrophysiological experiments to assess effects of different spinal cytokines and spinally applied cytokine-neutralizing compounds on responses of spinal neurons to noxious mechanical stimulation of the knee joint;
2. Assess the expression of cytokines and cytokine receptors in different cell types and the release of cytokines in spinal cord during arthritis (ELISA);
3. Define specific effects of cytokines on the activation of glial cells and neurons in suitable cell lines.

Definition of cytokine mediators of spinal hyperexcitability underlying joint pain.

Secondment(s): Eli Lilly (6 months). Examine cytokine effects on spinal excitability in spinal cord slices, and training on product development strategy, product launch & management and public relations.