Neurons in the central nervous system (CNS), which includes the eye, brain and spinal cord, fail to regenerate their axons after injury and in neurodegenerative diseases. The failure of retinal ganglion cells'(RGCs1) axons to traverse an injured optic nerve leads to permanent loss of vision. In the spinal cord, a similar failure leads to permanent loss of motor and sensory function. Thus the failure of CNS regeneration underlies a major clinical need. Over the prior 25 years, research has attributed this failure to the presence of negative, inhibitory, glial-associated substrates, as well as to a lack of sufficient positive, growth-promoting neurotrophic signals. Blocking inhibitory signals and providing neurotrophic factors can slightly enhance functional recovery, although typically only a few axons regenerate. It is known that trophic factors must be presented to the growth cone to stimulate axon elongation. Interestingly, direct mechanical tension will coax axonal growth cones to elongate independent of trophic factors, suggesting that trophic factors signal growth cones to create tension on the axon. After binding to their receptors, neurotrophic factors are rapidly endocytosed into 100-200 nm diameter """"""""signaling endosomes"""""""" and retrogradely transported intact down the axon to the cell body. If signaling endosomes were instead artificially held at the growth cone, could they more effectively stimulate axon growth? These questions have been difficult to address because of endosomes'nanometer scale. >We have identified two approaches by which magnetic nanoparticles could be used to manipulate axons to overcome inhibitory substrates and to enhance the trophic signaling of axon growth. Here we propose to design and validate the use of magnetic nanoparticles to enhance regenerative axon growth by RGCs by (1) directly manipulating mechanical tension on the growth cone after surface attachment of magnetic nanoparticles, and (2) directly manipulating localization of neurotrophic signaling in signaling endosomes inside RGC axons after endocytosis of magnetic nanoparticles. In our first two aims we will test magnetic nanoparticle size arid coatings to optimize surface binding (Aim 1) and endocytosis into signaling endosomes (Aim 2). In our third aim we will use these optimized magnetic nanoparticles to stimulate axon regeneration in cultured RGCs by application of external magnetic fields. Our long term goal at a basic science level is to better understand the interplay between trophic signaling and mechanical tension in axon growth, and at a translational level to develop nanotechnologies into therapeutic approaches for treating CNS-related diseases.
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| Hu, Ying; Cho, Seongeun; Goldberg, Jeffrey L (2010) Neurotrophic effect of a novel TrkB agonist on retinal ganglion cells. Invest Ophthalmol Vis Sci 51:1747-54 |
