Monday, December 30, 2024
12/30/2024
PROJECT SUMMARY Diabetic Retinopathy (DR) is the most common complication of diabetes and is the leading cause of vision loss in working-aged adults. DR is classified into non-proliferative DR and proliferative DR. In the non- proliferative stage, damage to retinal capillaries results in a lack of oxygen to the tissue. When capillary loss is significant, patients progress to the proliferative stage of disease, which is characterized by neovascularization, or growth of new blood vessels. These vessels do not function properly and cause bleeding into the retina and subsequent vision loss. While there are treatments for proliferative DR, there are none for non-proliferative DR, a stage at which vision loss could still be prevented for millions of patients. The lack of treatments is due to a lack of understanding of the underlying mechanisms that contribute to disease development. The literature demonstrates that inflammation may contribute to disease pathogenesis. C-chemokine ligand 2 (CCL2) is the most consistently elevated chemokine in intraocular patient samples from all stages of DR. Studies have also shown that leukostasis, or the firm attachment of leukocytes to the retinal vasculature, results in endothelial cell damage. However, there is a gap in knowledge in the field regarding how leukocytes promote capillary degeneration, which leukocytes are responsible, where this occurs, and which interactions between leukocytes and endothelial cells are necessary for DR pathogenesis. Investigating the inflammatory cascade beyond leukostasis could elucidate additional steps that can be targeted, reducing ischemia and thereby preventing vision loss from advanced disease. Based on the premise that static intravascular myeloid cells do not generally harm endothelial cells, but when they do (e.g. vasculitis) the damage is immediate and histologically obvious, our central hypothesis is CCR2-responsive myeloid cell transmigration is critical for DR progression, and blocking transmigration may prevent disease progression. We will test our hypothesis through two Specific Aims: (1) Determine whether and when blockade of CCL2-driven myeloid cell infiltration will halt the progression of inflammation in the mouse retina, and (2) Determine if blocking leukocyte-endothelial interactions early in the DR disease course can reduce DR progression. In Aim 1 we will use an acute model of inflammation induced by CCL2 intravitreal injections; in Aim 2 we will use a streptozotocin-induced diabetic mouse model. We will compare the effects of blocking leukocyte transmigration versus adhesion on DR progression, measured by markers of endothelial cell apoptosis, tight junction integrity, microglial activation, and leukostasis. We will adapt our intravital microscopy system to observe leukocyte dynamics in real time serially in the retinas of live mice with DR. The information obtained from this project will improve our understanding of the role of innate immunity on disease progression and aid in development of novel therapies for non-proliferative DR.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).