摘要
The strong repair and pro-survival functions of neurotrophins at their primary receptors, TrkA, TrkB and TrkC, have made them attractive candidates for treatment of nervous system injury and disease. However, difficulties with the clinical implementation of neurotrophin therapies have prompted the search for treatments that are stable, easier to deliver and allow more precise regula- tion of neurotrophin actions. Recently, the p75 neurotrophin receptor （p75wrR） has emerged as a potential target for pharmacological control of neurotrophin activity, supported in part by stud- ies demonstrating 1） regulation of neural plasticity in the mature nervous system, 2） promotion of adult neurogenesis and 3） increased expression in neurons, macrophages, microglia, astro- cytes and/or Schwann cells in response to injury and neurodegenerative diseases. Although the receptor has no intrinsic catalytic activity it interacts with and modulates the function of TrkA, TrkB, and TrkC, as well as sortilin and the Nogo receptor. This provides substantial cellular and molecular diversity for regulation of neuron survival, neurogenesis, immune responses and pro- cesses that support neural function. Upregulation of the p75^NTR under pathological conditions places the receptor in a key position to control numerous processes necessary for nervous system recovery. Support for this possibility has come from recent studies showing that small, non-pep- tide p75^NTR ligands can selectively modify pro-survival and repair functions. While a great deal remains to be discovered about the wide ranging functions of the p75^NTR, studies summarized in this review highlight the immense potential for development of novel neuroprotective and neu- rorestorative therapies.
The strong repair and pro-survival functions of neurotrophins at their primary receptors, TrkA, TrkB and TrkC, have made them attractive candidates for treatment of nervous system injury and disease. However, difficulties with the clinical implementation of neurotrophin therapies have prompted the search for treatments that are stable, easier to deliver and allow more precise regula- tion of neurotrophin actions. Recently, the p75 neurotrophin receptor （p75wrR） has emerged as a potential target for pharmacological control of neurotrophin activity, supported in part by stud- ies demonstrating 1） regulation of neural plasticity in the mature nervous system, 2） promotion of adult neurogenesis and 3） increased expression in neurons, macrophages, microglia, astro- cytes and/or Schwann cells in response to injury and neurodegenerative diseases. Although the receptor has no intrinsic catalytic activity it interacts with and modulates the function of TrkA, TrkB, and TrkC, as well as sortilin and the Nogo receptor. This provides substantial cellular and molecular diversity for regulation of neuron survival, neurogenesis, immune responses and pro- cesses that support neural function. Upregulation of the p75^NTR under pathological conditions places the receptor in a key position to control numerous processes necessary for nervous system recovery. Support for this possibility has come from recent studies showing that small, non-pep- tide p75^NTR ligands can selectively modify pro-survival and repair functions. While a great deal remains to be discovered about the wide ranging functions of the p75^NTR, studies summarized in this review highlight the immense potential for development of novel neuroprotective and neu- rorestorative therapies.
基金
supported by NIH Grants NS083164,MH085606 and F31 MH101019
