Diabetes causes both macro and micro-cerebrovascular diseases such as diabetic retinopathy, stroke and cognitive impairment. My long-term carrier goal is to establish a biomedical research career in the field of diabetic microangiopathy of the brain. Our group showed that diabetes increases pathological neovascularization as well as vascular remodeling in brain and eyes that differ from peripheral vascular insufficiency. Pericyte cells have a pivotal role in modulating microvascular physiology and pathological angiogenesis through the repression of endothelial cell proliferation, and modulation of capillary remodeling. Yet, the role of pericytes in diabetic microangiopathy remains big gab in our knowledge. My short-term goal is investigate the role and mechanisms by which pericyte cells contribute to diabetes-induced pathological neovascularization. My robust preliminary data suggest a switch towards a pro-angiogenic signal. While EphrinB2, a transmembrane ligand for ephrin (Eph) receptor tyrosine kinases that promotes angiogenic response and interaction between endothelial and pericytes is increased, there is a reduction of angiostatic signal characterized by decreased roundabout-4 (Robo-4), a vascular specific member of axonal guidance proteins expressed in endothelial cells that stabilizes blood vessels with its ligand Slit2. Recent findings showed that pericytes also express Robo-4. My central hypothesis is that pericytes play a crucial role in diabetes-mediated dysfunctional pathological cerebral neovascularization via dysregulation of Slit-2/Robo-4 and EphrinB2/EphB4 signaling. I propose 2 novel specific aims to test this hypothesis.Aim 1. Decreased Robo-4 signaling in pericytes contributes to pathological neovascularization in diabetes. Aim 2. Increased EphrinB2/EphB4 signaling disrupts pericyte and endothelial cell interaction leading to pathological neovascularization in diabetes. Successful completions of these studies will identify A) the role of pericytes in diabetes-induced pathological neovascularization; and B) angiostatic Robo-4 and proangiogenic EphrinB2 as novel therapeutic targets that can be used to manipulate pericyte/endothelial interaction and angiogenesis while providing a strong foundation for my future research as I begin my independent scientific career.
|Program type||Scientist Development Grant|
|Effective start/end date||07/01/2016 → 06/30/2019|