The long-term goal of this research is to discover the force-transduction molecules that initiate touch and pain in mammals. These senses are essential for social interactions and for avoiding harmful environments;however, in pathophysiological states, touch hypersensitivity contributes to allodynia and chronic pain. The objective of this application is to define sensory transduction mechanisms in Merkel cell-neurite complexes. These complexes are exquisitely sensitive touch receptors in the skin that encode shapes and textures, such as Braille-like patterns in humans. They are made up of epidermal Merkel cells and the terminals of somatosensory afferent neurons. This application focuses on mouse Merkel cell-neurite complex physiology because it is the mammalian touch receptor that is most amenable to in vitro and in vivo experiments. Although they are one of only four conserved cell types in the vertebrate epidermis, the role of Merkel cells in skin biology is still unknown. The central hypothesis of the proposed research is that epidermal Merkel cells are mechanosensitive cells that transduce force via ion channels. If true, the resulting electrical signals will be sent via sensory neurons to the brain to encode gentle touch. This hypothesis will be directly tested by combining physiological techniques (calcium imaging approaches and electrophysiology) to analyze force-activated signals in Merkel cells and molecular approaches to identify genes that encode mechanotransduction machinery. Simplified in vitro systems will be used to elucidate mechanotransduction molecules, and intact imaging will assess the touch-sensitivity of Merkel cells in vivo.
The specific aims are to: 1. Determine whether force-activated ion channels mediate mechanotransduction in Merkel cells. 2. Evaluate the contribution of extracellular tethers to touch sensitivity in Merkel cells. 3. Identify ion-channel subunits required for mechanotransduction in Merkel cells.
The application aims to identify genes essential for mechanotransduction in touch and pain receptors in the skin. When mechanosensation is disrupted by peripheral nerve damage, which accompanies a vast number of diseases (diabetes), infections (HIV) and medical interventions (chemotherapy), injuries often lead to permanent impairment that can necessitate limb amputation. Moreover, touch hypersensitivity is a common feature of chronic pain, a devastating public health problem afflicting >50 million Americans. By identifying the molecules that initiate neuronal signals that are 1) impaired in peripheral neuropathy and 2) overly active in chronic pain, these studies may provide molecular targets for the development of new therapeutics for these pathophysiological conditions.
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