MOLECULAR BASES OF NEURONAL CONNECTIVITY

Children'S Hospital Boston, Boston MA

Investigators

Linked publications & trials

Abstract

DESCRIPTION (adapted from applicant's abstract): Under normal circumstances, retinal ganglion cells are unable to regenerate their axons after injury. Damaged axons show only abortive sprouting at the site of injury, and after a few days, cells begin to die. However, minor injury to the lens produces signals that stimulate numerous ganglion cells to survive axotomy and to regenerate their axons through the optic nerve, a territory generally viewed as being inhibitory to growth. Lens injury activates resident microglia and infilitrative macrophages. These cells are known to exert multiple effects on injured neurons, some beneficial and others destructive. Specific Aim 1 will investigate whether the axon-promoting effects of lens damage in the rat are mediated through microglia, macrophages, or other cell types, and will determine whether specific aspects of this response can be altered to enhance ganglion cell survival and axon growth even further. Complementary studies in Aim 2 will examine if cell survival and axon regeneration stimulated by lens puncture can be augmented by treatments that increase intracellular levels of the second messenger, cyclic AMP, or that prevent the formation of a glial scar at the lesion site. At a more basic level, Aims 3 and 4 will investigate the molecular mechanisms that control axon outgrowth in retinal ganglion cells. Research in lower vertebrates has shown that AF-1, a small factor secreted by optic nerve glia, induces retinal ganglion cells to express a constellation of growth-associated genes and to extend lengthy axons. Glial cells of the mammalian peripheral nervous system are highly supportive to axon growth, and make a low molecular weight growth factor similar or identical to AF-1. Aim 3 will investigate the role of mammalian AF-1 in optic nerve regeneration in higher vertebrates. Finally, studies in lower vertebrates also show that one of the intracellular steps leading to axon outgrowth involves a purine-sensitive mechanism. To investigate the role to this kinase in controlling axon outgrowth in mammalian retinal ganglion cells, Aim 4 will isolate the kinase, clone its gene, and investigate its' significance for optic nerve regeneration by constructing dominant-negative mutants and examining its role in controlling gene expression. These studies will provide new insights into the basic mechanisms that control axon growth in the primary visual pathway, and enhance our ability to restore visual function after injury or in glaucoma.