Stefan's Website
All hearing sensation is derived from the electrical output of a remarkably small number of sensory cells: fewer that 15,000 per inner ear at birth. These hair cells are the mechanoelectrical transducers of the inner ear: deflections of the sterociliary bundles on their apical surfaces lead to transmitter release from their basolateral poles, leading, in turn, to signal generation in the peripheral axons of the auditory nerve fibers.Most types of congenital and acquired hearing loss arise from damage to, or loss of, these sensory cells or their associated neurons. The incidence of heritable deafness is high: one child in a thousand is born deaf; another one in a thousand becomes deaf before adulthood. The prevalence of acquired hearing loss is rising, as the population ages, and as noise pollution steadily increases. It is estimated that one in three adults over the age of 65 has a handicapping hearing loss, and this impairment is largely due to the irreversible loss of sensory cells.Underlying the irreversibility of hearing loss in mammals is the incapacity to replace lost hair cells by cell division or by regeneration from endogenous cells in the inner ear epithelia. Hair cell replacement, either by stimulation of regeneration (as occurs naturally in non-mammalian vertebrates) or by transplantation of progenitor cells capable of differentiating into hair cells, remains therefore the ultimate goal in the development of treatment applications to reconstruct the damaged inner ear.
Mechanoreception - Osmosensation - TRPV4
Mechanosensitive ion channels are probably utilized by most cells to respond to stretch of their membranes, generated during movement or by changes in a cell's volume. Multicellular organisms have organs that are specialized in detecting mechanical forces generated by changes in osmotic pressure, touch, tension in tissues, gravity, or sound. The circumventricular organs in the brain, for example, lack a blood-brain barrier and are therefore able to directly measure the osmolality of the blood. The neurosensory cells of these organs that express the appropriate mechanoreceptors are able to communicate to neurosecretory cells leading to the secretion of antidiuretic hormone. Another example is the hair cells of the inner ear that detect direct mechanical stimulation with a highly specialized organelle, the hair bundle. A third example is mechanosensitive sensory ganglion neurons that mediate peripheral nervous system responses to touch and mechanical pain.The research in our laboratory is focused on the identification of mechanosensitive ion channels that are responsible for osmosensation and direct mechanosensation. Furthermore, we seek to learn how mechanosensitive ion channels work.By employing a candidate-gene approach based on the invertebrate gene Osm-9 andrelated Trp genes, we have cloned the vanilloid receptor-related osmotically activated channel (VR-OAC, TRPV4). This novel cation-selective channel is gated by mechanical force and by exposure to hypotonic solutions within the physiological range of plasma osmolality. Because the channel is expressed in key neurosensory cells, including inner-ear hair cells and neurons of circumventricular organs and sensory ganglia, VR-OAC (TRPV4) is a strong candidate to mediate mechanical and osmotic responsiveness in vertebrates.
