Research in my laboratory is focused on the biology of sensory neuron development and recovery from disease. Sensory neurons are powerfully regulated during development by endogenous neurotrophic factors. However, these neurotrophic factors may also have great potential to regulate neurons in adulthood and thus serve as potential therapeutic agents. Our long-term objective is to characterize the cellular and molecular actions of neurotrophins on sensory neurons in order to understand how neurotrophins may improve sensory impairments. Our research involves two different populations of neurons: large myelinated proprioceptive neurons and small unmyelinated nociceptive neurons. Proprioceptive neurons respond to neurotrophin-3 (NT-3) and we anticipate that NT-3 will be effective in the treatment of disorders that involve large myelinated sensory fibers. This project uses two experimental paradigms that compromise proprioceptive neurons: peripheral nerve injury and neuronal degeneration in disease. We utilize three mouse models: NT-3 transgenic, NT-3 null mutant, and hereditary mutant mice that undergo degeneration of NT-3-dependent proprioceptive neurons. These animal models are used to study the trophic support of neurons following perturbation in vivo, and to explore the extent of NT-3's therapeutic effects. Nociceptive neurons respond to either nerve growth factor (NGF) or glial cell line-derived factor (GDNF). New evidence now links impaired trophic support to neuropathic neuronal deficits of nociceptive neurons, leading to abnormal gene expression and abnormal regeneration. One neuropathic condition includes diabetic neuropathy, which is a serious neuronal complication that develops in many diabetic patients. Our current studies are designed to understand the response(s) of nociceptive sensory neurons in a mouse model of experimental diabetes. The goal is to define the role of these neurotrophins in this disease in order to design better treatments for peripheral neuropathies.