Chronic inflammation and oxidative stress are hallmarks of many age-related diseases, including cardiovascular disease. There is a critical need to establish the molecular and cellular basis for the increased and sustained inflammatory and oxidative status that leads to vascular disease. We have recently shown that the scaffolding protein Ezrin Binding Protein 50 (EBP50, also known as NHERF1) is a key regulator of systemic and vascular inflammation. Studies in mice and in cell systems show that inflammatory stimuli promote EBP50 expression in macrophages and vascular smooth muscle cells (VSMC) and, conversely, EBP50 increases inflammatory responses in these cells. Preliminary studies also indicate that EBP50 increases the generation of reactive oxygen species and potentiates oxidative stress in vessels. These findings suggest a novel and pathologically relevant role for EBP50 in the control of both inflammation and oxidative stress. We hypothesize that EBP50 promotes a chronic inflammatory and oxidative status that contributes to atherosclerosis and vascular disease.
Three specific aims are designed to test this hypothesis and elucidate the molecular mechanisms underlying these novel actions of EBP50.
In Aim 1 that molecular mechanisms by which EBP50 regulates oxidative stress will be elucidated.
Aim 2 will determine the actions of EBP50 that regulate mitochondrial function and the responses to inflammatory and oxidative stimuli.
In Aim 3, murine models will be used to determine the effect of EBP50 on neointima formation. This research plan employs complementary methods to define a novel mechanism by which EBP50 regulates inflammation and oxidative stress. The long-term goal is to identify and exploit novel avenues for pharmacological intervention aimed at limiting chronic inflammation and oxidative stress.
Cardiovascular disease is one of the most common diseases. Atherosclerosis, in particular, is a significant public health issue and complications from this disease (including restenosis) are one of the most important causes of morbidity and mortality. The adaptor protein EBP50 contributes to the establishment of the chronic inflammatory and oxidative status that leads to the development of neointimal hyperplasia. This proposal aims at determining the role of EBP50 in neointima formation using cell-based and murine systems. These studies will provide the mechanistic basis to further advance our understanding of vascular remodeling and will lead to the identification of novel therapeutic targets for the prevention and treatment of inflammatory vascular diseases.
| Zhang, Qiangmin; Xiao, Kunhong; Liu, Hongda et al. (2018) Site-specific polyubiquitination differentially regulates parathyroid hormone receptor-initiated MAPK signaling and cell proliferation. J Biol Chem 293:5556-5571 |
