Liver X Receptor (LXR) as a Novel Therapeutic Target in Diabetic Retinopathy (DR)

Diabetic retinopathy (DR) is a disabling microvascular complication. Despite recent advances
using pharmacotherapy, a cure for DR has yet to be realized. Thus, a conceptual and technical
breakthrough to identify novel targets, and a strategy to cure this complication is
paramount. We believe that the recent clinical evidence from large clinical trials
demonstrating a strong association between lipid abnormalities and DR progression and the
discovery that activation of the nuclear hormone receptors liver X receptors (LXRα/LXRβ)
prevents DR in rodent models offers such a breakthrough. The detrimental effect of
dyslipidemia is not limited to the vasculature but also leads to dysfunction of circulating
angiogenic cells (CAC) and of macrophages. The endogenous ligands for LXRs are oxidative
metabolites of cholesterol that serve as intracellular cholesterol "sensors". LXR agonists
operate, in part, by transcriptional upregulation of genes involved in promoting cholesterol
efflux and inhibition of cholesterol uptake; and by inhibiting inflammation. Our published
studies and new preliminary data show that pharmacological LXR activation prevents DR
development in both T1D and T2D rodent models. In this application, we seek to understand the
mechanisms involved in this beneficial effect. We put forth the hypothesis that LXR
activation will restore cholesterol homeostasis in the diabetic retina and correct
diabetes-induced bone marrow dysfunction to sustain CAC levels and function and to reduce of
myeloid cell production.

Inclusion Criteria:

- Any man or woman between the ages of 21- 98 years of age will be eligible to
participate. To participate in the study as a study subject we will require: a) the
subject must either carry the diagnosis of diabetes or be a healthy aged control and
b) the patient be willing and have the ability to cooperate with the protocol.

Exclusion Criteria:

- Exclusion criteria: We will apply the following exclusion criteria: a) evidence of
ongoing acute or chronic infection (HIV, Hepatitis B or C, tuberculosis); b) ongoing
malignancy; c) cerebral vascular accident or cerebral vascular procedure; d) current
pregnancy; e) history of organ transplantation; f) presence of a graft (to avoid any
effect of the graft on inflammatory parameters; g) uremic symptoms, an estimated
glomerular filtration rate of less than 20 cc/min (by Modification of Diet in Renal
Disease equation), or an albumin of less than 3.6 (to avoid malnutrition as a
confounding variable); h) be unwilling to abstain from drinking alcohol and i)
patients with anemia. Subjects with AMD, glaucoma, uveitis, known hereditary
degenerations or other significant ocular complications other than diabetic
retinopathy will be excluded.