Research problem:
Diabetic retinopathy is a major complication of diabetes and the leading cause of blindness among working
adults worldwide. The prevalence of diabetic retinopathy is increasing, and it is predicted to double over
the next 30 years, both worldwide and in Saudi Arabia. There is no treatment for the early stages of
diabetic retinopathy. Late-stage retinopathy (proliferative retinopathy) can be treated with invasive
procedures that seal abnormal blood vessels and combat inflammation, but this treatment has limited
benefits. The growing incidence of diabetic retinopathy demands new approaches that increase our
understanding of the pathophysiology of the disease and that improve detection, prevention and treatment
at the earliest stage of the disease, rather than waiting for the onset of vision-threatening lesions.
Objectives:
The overall objective of this proposal is to elucidate the cellular and molecular mechanisms of diabetic
retinopathy by detecting key metabolites/factors involved in the disease progression to identify molecular
targets for early intervention. The first major objective will be to analyze the metabolites and neurotrophic
factors in sera from diabetic patients and in vitreous from proliferative diabetic retinopathy patients. The
second objective is to determine the level of metabolites and neurotrophic factors in the retinas and sera of
rats with streptozotocin-induced diabetes. The third objective is to analyze the effect that dysregulated
metabolites on the expression of neurotrophic factors and signaling in neurodegenerative pathways in
cultured retinal cells.
Scientific approaches:
First, we will determine the levels of metabolites and neurotrophic factors in serum from diabetic and
diabetic retinopathy patients and compare them with those from nondiabetic patients. Second, we will
measure the metabolites and neurotrophic factors in the serum and retinas from diabetic rats and compare
them with those from nondiabetic controls. Third, we will determine the effect of those metabolites on
retinal cells and analyze the regulation of the neurotrophic factors and the signaling mechanism involved in
neurodegenerative pathways.
Research methodologies:
For objectives 1 and 2, we will measure the metabolites and neurotrophic factor levels using biochemical,
HPLC and ELISA techniques. For Objective 3, we will analyze the expression and regulation of those
neurotrophic factors using ELISA and immunoblotting techniques and will use biochemical analysis to
measure oxidative stress and apoptosis in metabolite-treated retinal cells, as described in the methodology
section.
Expected results:
We expect that results from this proposed study will identify metabolite(s)/neurotrophic factor(s) as
potential biomarkers that can damage retinal neurons and will provide a molecular indication of early
neurodegeneration in the diabetic retina. Targeting disrupted metabolic or neurotrophic factors and the
signaling through them in the diabetic retina could provide therapeutic approaches that ameliorate neuronal
damage, the earliest sign of diabetic retinopathy. Neuronal damage leads to microvascular damage later in
diabetic retinopathy, which is the leading cause of blindness in Saudi Arabia and worldwide. In addition,
this research will create infrastructure and will train personnel and students for cutting-edge molecular cell
biology research. Furthermore, this research will increase productivity by publishing research findings in
peer-reviewed, reputable journals.