GOLPH3 in vascular smooth muscle cell biology and vascular disease

GOLPH3 在血管平滑肌细胞生物学和血管疾病中的作用

• 批准号: 9327041
• 负责人: chunxiang Zhang
• 金额: $ 36.75万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-05 至 2020-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9327041
• 关键词: Acute; Affect; Anabolism; Animals; Aorta; ApoE knockout mouse; Apoptosis; Area; Arteries; Atherosclerosis; Biological; Biological Process; Blood Vessels; Cancer Prognosis; Cardiovascular Diseases; Cardiovascular system; Carotid Arteries; Cell Differentiation process; Cell Proliferation; Cell model; Cell physiology; Cells; Cellular biology; Chronic; Colorectal Cancer; Coronary Arteriosclerosis; Cytoplasmic Organelle; Data; Development; Disease; Esophageal; Eukaryotic Cell; Event; FRAP1 gene; GOLPH3 gene; Goals; Golgi Apparatus; Growth; Human; In Vitro; Injury; Lead; Lipids; Malignant Neoplasms; Malignant neoplasm of lung; Malignant neoplasm of ovary; Mediating; Membrane; MicroRNAs; Molecular; Mus; Muscle Cells; Neoplasm Metastasis; Pancreatic Adenocarcinoma; Pathogenesis; Pathologic; Pathway interactions; Platelet-Derived Growth Factor; Play; Primary carcinoma of the liver cells; Proteins; Proteome; Proteomics; Rattus; Research; Role; Scientist; Serum; Signal Pathway; Societies; Sorting - Cell Movement; Stroke; Subfamily lentivirinae; Testing; Time; Up-Regulation; Vascular Diseases; Vascular Proliferation; Vascular Smooth Muscle; atherogenesis; base; cancer cell; cell dedifferentiation; gain of function; improved; in vivo; injured; interest; knock-down; loss of function; malignant breast neoplasm; malignant stomach neoplasm; migration; negative affect; new therapeutic target; novel; novel therapeutics; public health relevance; small hairpin RNA; vascular smooth muscle cell proliferation

 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.

 描述(申请人提供)：高尔基体(也称为高尔基复合体或高尔基体)是一种重要的细胞质细胞器，因其在脂质和蛋白质的生物合成、运输和分类中的关键作用而引起所有科学家的极大兴趣。作为这些重要作用的结果，其蛋白质组的任何变化都会对其功能产生负面影响，进而导致许多疾病。高尔基体磷酸蛋白3(GOLPH3)是2000年通过高尔基体蛋白质组学鉴定的一种高度保守的34 kDa蛋白质，位于高尔基体膜和细胞质池中。在过去的5年里，GOLPH3已经成为研究的热点，因为它在许多癌症中都被发现具有强大的生物学功能。虽然GOLPH3是真核细胞中的一个关键分子，在许多癌症的发病机制中也是一个关键分子，但还没有研究确定它在心血管细胞生物学和心血管疾病中的作用。这项建议的目的是确定GOLPH3在血管平滑肌细胞(VSMC)生物学和增殖性血管疾病中的生物学作用。我们的初步研究首次证实GOLPH3在VSMCs和血管壁高表达，在增殖期VSMCs、球囊损伤大鼠颈动脉、 动脉粥样硬化的小鼠动脉和动脉粥样硬化的人动脉。此外，GOLPH3对VSMC的增殖也有很强的促进作用。根据我们的初步数据，我们假设LIN-28/let-7d星轴参与了增生性VSMCs和增殖性血管疾病的血管壁中GOLPH3的上调。GOLPH3通过其下游信号通路Akt/mTOR，在VSMC细胞功能、血管新生内膜生长和动脉粥样硬化的发生发展中发挥重要作用。我们的假设得到了初步数据的支持。我们将通过以下三个特定目标进一步验证这一新假说：特定目标1测试GOLPH3对体外培养的VSMCs的去分化、增殖、迁移和凋亡的影响；特定目标2确定GOLPH3对VSMCs的细胞功能、血管损伤诱导的急性血管内膜生长和体内慢性动脉粥样硬化的影响；以及特定目标3确定GOLPH3在体外和体内对VSMCs的细胞作用和血管对增生性血管疾病的影响的分子机制。本研究通过分析一个新的动脉粥样硬化信号通路LIN-28/let-7d STAR/GOLPH3/Akt/mTOR，为动脉粥样硬化的发病机制提供新的分子机制。GOLPH3可能成为治疗动脉粥样硬化性血管疾病的新靶点。