Project Abstract or Summary
Following injury to the optic nerve in mammals, retinal ganglion cells (RGCs) cannot regenerate their axons and
soon undergo apoptotic cell death, leading to permanent vision loss. Some degree of optic nerve regeneration
can be induced experimentally but the extent of regeneration achieved to date remains away from the level of
visual functional recovery required, pointing to the need for more effective therapies. Aside from testing well
established growth factors and chance discoveries of several novel factors, a more systematic screening of as
yet untested ligands to the many trophic factor and chemokine receptors that are expressed in adult RGCs could
augment regeneration well beyond currently achievable levels. In recent genetic studies (RNA-Seq, FACS-
purified cells), we have obtained an extensive list of growth factor, chemokine and peptide receptors that are
expressed in adult RGCs, many of whose ligands have not been tested for effects on axon regeneration and
RGC protection. To carry out the screening, we will use an adult RGC culture system and in vivo optic nerve
regeneration models that have been used on our lab for 2 decades, and which have enabled us identify three
previously unknown potent factors for optic nerve regeneration. The proposed studies will screen the ligands to
the multiple receptors that are expressed in adult RGCs to discover novel factors for optic nerve regeneration
and RGC survival. With significantly improved automated cell culture system, Aim 1 will carry out an in vitro
bioactivity screen and verify hits in vivo, respectively. Aim 2 will screen which subtypes of RGCs are responding
to the known effective treatments and the new hits from Aim 1. This will enable us develop combinatorial
treatments to stimulate axon regeneration from multiple RGC subtypes simultaneously. Through these studies,
we expect to promote considerably greater levels of axon growth than can be attained currently and ultimately
bring us closer to improving visual function after optic nerve damage.