GOLPH3 in vascular smooth muscle cell biology and vascular disease

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 DESCRIPTION (provided by applicant): The Golgi apparatus (also known as the Golgi complex or Golgi body) is an important cytoplasmic organelle that is of great interest to all scientists for its key roles in the biosynthesis, transporting and sorting of both lipids and proteins. As a consequence of these important roles, any changes in its proteome can negatively affect its functions and in turn lead to many diseases. Golgi phosphoprotein 3 (GOLPH3) is a highly conserved 34-kDa protein initially identified in 2000 through proteomic characterizations of the Golgi apparatus, which is located at the Golgi membrane as well as in the cytosolic pool. In the past 5 years, GOLPH3 has become a hot research area, because its strong biological functions are identified in many cancers. Although GOLPH3 is a critical molecule in eukaryotic cells and in the pathogenesis of many cancers, no studies have been performed to determine its roles in cardiovascular cell biology and cardiovascular disease. The goal of this proposal is to determine the biological roles of GOLPH3 in vascular smooth muscle cell (VSMC) biology and in proliferative vascular disease. Our preliminary studies have identified for the first time that GOLPH3 is highly expressed in VSMCs and vascular walls, and its expression is significantly increased in proliferative VSMCs, balloon-injured rat carotid arteries, atherosclerotic mouse aortas and atherosclerotic human arteries. In addition, GOLPH3 has a strong effect on VSMC proliferation. Based on our preliminary data, we hypothesized that the Lin-28/Let-7d star axis is involved in the up-regulation of GOLPH3 in proliferative VSMCs and in vascular walls with proliferative vascular disease. GOLPH3 is a critical novel molecule in VSMC cellular functions and in the development of vascular neointimal growth and atherosclerosis via its downstream signaling pathway, Akt/mTOR. Our hypothesis is supported by our preliminary data. We will further test this novel hypothesis by the following 3 Specific Aims: Specific Aim 1 i to test the effects of GOLPH3 on the dedifferentiation, proliferation, migration and apoptosis of cultured VSMCs in vitro; Specific Aim 2 is to determine the effects of GOLPH3 on cellular functions of VSMCs, acute vascular neointima growth induced by vascular injury, and chronic atherosclerosis in vivo; and Specific Aim 3 is to determine the molecular mechanisms responsible for GOLPH3-mediated cellular effects on VSMCs and vascular effects on proliferative vascular disease both in vitro and in vivo. The study will provide a new molecular mechanism of atherosclerosis by analysis a novel atherosclerosis signaling pathway Lin-28/Let-7d star/GOLPH3/Akt/mTOR, which is centralized by the abundant Golgi protein, GOLPH3. GOLPH3 may be a novel therapeutic target for atherosclerotic vascular disease.