Mechanisms of Tinnitus

Keywords; Tinnitus, in vivo skills
Abstract:This PhD proposal is a collaboration between the Institute of Neuroscience at Newcastle University and Autifony Therapeutics. The aims of the project are to investigate mechanisms that underlie tinnitus, and to determine if these changes are reversed by a novel drug developed by Autifony.

Autifony Therapeutics is a small, focused UK-based pharmaceutical company formed as a spin-out from GlaxoSmithKline. It has offices in London, and labs in Verona, Italy. The company consists of a dedicated team of scientists, clinicians, and business development personnel with a portfolio focussing on drugs to treat hearing disorders (including tinnitus), and schizophrenia.

Tinnitus, the hearing of phantom tones or noise, afflicts up to 15% of the population. In 3% of the population it is sufficiently severe to seriously affect quality of life. It can lead to isolation and depression with their consequent burdens on health-care and the economy. Tinnitus is usually associated with hearing loss, so is a growing problem in an increasingly ageing population. But tinnitus can also be induced by excessively loud sounds, such as amplified music, gunfire or explosions resulting in an increased incidence amongst younger adults. There is currently no pharmacological treatment or cure for tinnitus. Research to understand the mechanisms responsible for tinnitus has increased in recent years with the development of better animal models and non-invasive imaging methods in humans. It is known that in people with tinnitus, nerve cells in the auditory regions of the brain become over active and fire impulses at abnormally high rates in the absence of sound.

This project addresses why such over-activity occurs, and how a new drug developed by Autifony, shown to reduce tinnitus in animals and now in clinical trials, reduces this aberrant neural firing. This drug enhances the activity of a type of channel called Kv3.1 which is found in the membrane surrounding nerve cells. Kv3.1 regulates the electrical properties of the nerve cells and helps to control when they fire impulses.

We aim to test hypotheses that explain how Kv3.1 channels become abnormal in tinnitus by studying the properties and distribution of these channels in nerve cells in the midbrain centre of the auditory pathway. We will do this in normal rats and in rats in which we have induced tinnitus (verified using a behavioural test). The student will use several techniques that enable us to measure the activity of Kv3.1 channels. These include using a selective marker that enables us to visualise, under a microscope, where the channels are located and whether they are in an activated (de-phosphorylated) state. In Newcastle we will also make recordings using fine electrodes implanted in the midbrain of anaesthetised rats so enabling us to record the responses of nerve cells to sound patterns that signal the operation of Kv3.1. At Autifony's labs the student will learn a complementary method for recording inside single nerve cells in brain slices to test the function of Kv3.1 channels. In addition to testing these properties in normal rats and rats with tinnitus, we will study how Autifony's compound modulates the responses of nerve cells in the two groups of animals.

The project will cement a recently established link between Newcastle University and Autifony and involves mutually-complementary expertise. It offers the student an advanced, multidisciplinary training in neuroscience, including in one of the MRC's priorities areas - whole organism research - under experienced supervisors. The student will gain experience of science in an academic and company setting, and learn about the business side of drug discovery and development. In total, the PhD project will provide an excellent foundation for a future scientific career in medical research.