Almost 25% of the veterans that are currently receiving healthcare through the VA system carry the diagnosis of diabetes. Nearly all veterans with type 1 diabetes and >60% of veterans with type 2 develop retinopathy during the first two decades of disease, 1% will experience severe visual loss or blindness. Current therapies provide clinically meaningful improvement in only 50% of veterans. Thus, there is a critical need to identify regulators of DR, which can be targeted therapeutically and will directly benefit a large group of veterans. We hypothesize that the multifunctional Ca2+/calmodulin-dependent kinase II (CaMKII) under hyperglycemic conditions promotes the endothelial pathology characteristic for diabetic retinopathy (DR), in particular endothelial apoptosis and barrier dysfunction. Thus, CaMKII inhibition may be a potent novel approach to prevent or treat DR. The long-term goal of the Grumbach lab is to study the function of CaMKII in the vasculature, specifically CaMKII modulation as a new approach to treat vascular disease. The objective of this project is to determine whether specific CaMKII inhibition in endothelium prevents non-proliferative DR. The central hypothesis is that CaMKII inhibition decreases non-proliferative DR by preventing endothelial apoptosis and barrier dysfunction, two key phenotypes of non-proliferative DR. We will test the hypothesis in a novel in vivo mouse model in which the potent and specific endogenous CaMKII inhibitor CaMKIIN is selectively overexpressed in endothelium and dissect molecular mechanisms in vitro. The rationale for the proposed studies is that, understanding whether CaMKII regulates the phenotypic changes of non- proliferative DR in vivo and drives endothelial cells ROS-production, apoptosis and barrier function may be a critical first step towards designing a specific CaMKII inhibitor to prevent and alleviate DR. We will test our central hypothesis in two specific aims: 1) Determine the role of endothelial CaMKII on non-proliferative DR in vivo, 2): Characterize whether CaMKII controls endothelial dysfunction under high glucose conditions in vitro. In the first aim, the novel in vivo model will be used to test whether CaMKII inhibition wil preserve retinal microvascular structure and function in non-proliferative DR.
Under aim 2, we will define the mechanisms through which CaMKII is activated under hyperglycemia and regulates barrier function, apoptosis and ROS production in vitro. The approach is innovative because of its use of novel in vivo models and imaging techniques and specific tools to dissect CaMKII signaling. The proposed research is significant because it is expected to advance the field by defining CaMKII as a novel molecular target that controls endothelial phenotypes in DR. Ultimately, such knowledge may allow for the development of new therapeutic strategies in DR that will benefits our veterans.
About 25% of Veterans receiving medical care from VA facilities have diabetes. Nearly all veterans with type 1 diabetes and >60% of veterans with type 2 develop retinopathy during the first two decades of disease. Diabetic retinopathy (DR) accounts for ~17% of cases of total blindness in the US and is the most frequent cause of blindness among adults aged 20-74. The proposed research aims at providing pilot data for a recently discovered key regulator of blood vessel function with the ultimate goal to develop its inhibitor as new treatment strategy to prevent the blood vessel changes leading to DR. The proposed research is directly relevant to VA Healthcare because of the high disease burden and enormous health care cost that DR is causing in veterans. In particular, it is relevant to the VA RR&D mission that has identified the early detection and treatment of potential blinding disorders of the Veteran as a main focus.
