BLR&D Research Career Scientist Award

The long-term goal of this vision research program is to gain a better understanding of 1) the mechanisms
underlying retinal synaptic and cellular physiology mediating visual image processing, and 2) the early
cellular changes that are likely to mediate ganglion cell death and loss of vision following retinal and optic
nerve disease and trauma. This program consists of two related components.
1) National Institute of Health supported studies are concerned with the functional organization of the
mammalian retina by investigating synaptic and cellular mechanisms, and the role of retinal microcircuits in
mediating image processing. This fundamental experimental component is focused on two classes of retinal
interneurons, called amacrine and horizontal cells, their network connectivity, and the action of their
signaling molecules that play a role in defined retinal circuits. These studies aim to advance our knowledge
of normal cellular mechanisms mediating visual information processing in the retina. This information is key
to understanding the pathophysiology of eye diseases, a required step for developing rational genetic and
stem cell therapeutic approaches for preventing or treating retinal diseases such as glaucoma, macular
degeneration, and diabetic retinopathy, which affect the Veteran population.
2) VA supported studies are concerned with understanding early mechanisms underlying retinal ganglion
cell death due to retina and optic nerve disease and injury. Ocular trauma, which frequently occurs with
traumatic brain injury (TBI), results in severe visual impairments, including acuity loss, photophobia, and
partial and total loss of vision. The current Merit Review is focused on Ca2+ channel and calcium permeable
AMPA receptor (CP-AMPAR) transcriptional and translational regulation and ganglion cell intracellular Ca2+
following optic nerve injury, as a model for optic nerve trauma. The first group of studies is focused on L-
type Ca2+ channels expressed by ganglion cells, to elucidate the actions of the L-type Ca2+ channel blocker,
lomerizine, which enhances ganglion cell survival in different models of optic neuropathy. Studies are
evaluating L-type Ca2+ channel expression and function following optic nerve injury, and to test the idea that
lomerizine blocks up-regulated Ca2+ channel function, which in turn slows intracellular retinal ganglion cell
Ca2+ influx. This in turn would limit pathological changes including ganglion cell loss. Animal studies testing
lomerizine administration on retinal ganglion cell survival are also planned. Related experimental studies
are focused on testing if CP-AMPARs, which are reported to be rapidly up-regulated on retinal ganglion cell
dendrites after ocular injury, mediate Ca2+ uptake into ganglion cells and contribute to ganglion cell death.
Experiments are focused on defining CP-AMPAR and the AMPAR editing enzyme expression, and testing
the idea that pharmacological antagonism, genetic and siRNA-mediated regulation of CP-AMPARs and the
AMPA editing enzyme ADAR2 stabilize ganglion cell intracellular Ca2+ levels, and enhances ganglion cell
survival following nerve injury. Animal studies will also test if selective CP-AMPAR antagonists and targeted
siRNAs protect against retinal ganglion cell loss after optic nerve injury.
The long-term goal of the Merit Review studies is to understand how vision loss associated with retinal
ganglion cell death can be reduced. These studies have the potential impact of unveiling novel therapeutic
approaches to ameliorate ocular damage and vision loss. These investigations are consistent with the
health-related goals of the Department of Veteran Affairs to develop effective treatments for eye injuries.

Grant Number: 5IK6BX005230-06
NIH Institute/Center: VA
Principal Investigator: NICHOLAS BRECHA