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 Investigator:
Maria Grant
Our long-range goal is to identify feasible approaches
for systemic (total body) or local retinal (eye) therapies that
can halt or prevent damage from new blood vessel growth (retinal
neovascularization) in the eyes of patients with proliferative diabetic
retinopathy. Proliferative diabetic retinopathy is the leading cause
of blindness in adults and children. Considerable evidence points
to a small, naturally occurring molecule called adenosine as a key
factor in signaling blood vessel cells, called endothelial cells,
to grow abnom1ally and fom1 new blood vessels. Like most other cells,
endothelial cells have special "receptor" molecules on their surfaces.
When adenosine attaches to its specific receptor, it can send a
series of signals to the cell that may change the cell' s behavior.
We have found that the endothelial cells that fom1 these new blood
vessels in the retina have higher than nom1al levels of adenosine
receptors.
In this proposal we aim to define the way(s) in which
adenosine acts on cells of the retinal blood vessels. We will examine
the effects of inhibiting adenosine's actions using a mouse model
of retinal neovascularization that is similar to that observed in
patients with diabetes. One way we will test this is by using ribozymes.
Ribozymes are small synthetic RNA molecules that can cut apart other
RNA molecules in a specific way. Because the receptor for adenosine
must be made from a specific RNA molecule, we can target the destruction
of adenosine receptors to detem1ine whether this strategy might
inhibit retinal neovascularization in mice.
Another consideration is the origin of endothelial
cells that fom1 these new blood vessels in the eye. We will examine
whether new endothelial cells arising from the bone marrow (also
called angioblasts or endothelial precursor cells) are more important
to neovascularization than endothelial cells already present in
the retina. To accomplish this we will use another mouse model.
In this model, special diabetic mice undergo a bone marrow transplant
with cells that have been genetically engineered to glow with a
green color. We can then tell the origin of the cells that fom1
new retinal blood vessels by whether or not they glow green. This
part of the project is unique in that it challenges our current
thinking about the source of cells responsible for the new blood
vessels in the retina.
Determining the origin of endothelial cells responsible
for retinal neovascularization is critical to developing non-destructive
therapies to treat the condition. Thus, eliminating adenosine receptors
from endothelial cells, along with discovering the true source of
cells that fom1 these new blood vessels, can lead to more effective
and less destructive anti- angiogenic therapies for diabetic retinopathy.
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