Mechanisms of Varicose Vein Formation

描述（由申请人提供）：静脉曲张是一种局灶性血管扩张，在高达30%的成人人群中存在，并且明显与显著的发病率相关。尽管与该综合征相关的患病率和显著的医疗保健费用，但缺乏旨在确定静脉曲张和慢性静脉功能不全机制的科学研究。在初步数据中，静脉疾病的进展与通常与脂肪细胞去分化相关的20多个脂蛋白相关基因的显著减少相关。已知参与骨骼肌中泛素依赖性蛋白质降解的基因也有所增加。因此，该提案的中心假设是，静脉中平滑肌细胞的变性和解体通过以下方式损害血管壁结构的完整性：（1）影响平滑肌细胞增殖的脂蛋白代谢变化和（2）调节蛋白质降解，导致平滑肌蛋白质降解和重塑。我们建议：1）表征在早期静脉疾病中观察到的变化，特别是脂质代谢相关蛋白的改变，并确定它们对平滑肌细胞完整性的贡献; 2）研究有助于静脉曲张中蛋白水解依赖性平滑肌细胞变化和结构完整性丧失的机制;和3）在静脉高血压的长期模型中检查脂蛋白代谢和泛素-蛋白酶体途径的相关性。总之，本提案将使用分子、组织学和体内研究的组合来定义有助于静脉曲张和慢性静脉功能不全发展的机制，以及建立研究潜在治疗所需的模型。虽然静脉疾病的发展是多因素的，但触发早期疾病以及进展为慢性疾病的关键过程尚不清楚。该申请将研究一种非常常见的血管疾病，目前没有任何NIH资助的项目正在调查，并将允许申请人利用他们在血管生物学，外科研究技能方面的基本兴趣以及他们在静脉曲张治疗方面的临床兴趣。

DESCRIPTION (provided by applicant): Varicose veins are focal vessel dilitations present in up to 30% of the adult population and clearly associated with significant morbidity. Despite the prevalence and marked health care costs associated with this syndrome, there has been a paucity of scientific studies aimed at defining the mechanism(s) responsible for varicosities and chronic venous insufficiency . In preliminary data, progression of venous disease was associated with a marked decrease in over twenty lipoprotein related genes normally associated with adipocyte dedifferentiation. There was also an increase in genes known to be involved in ubiquitin-dependent protein degradation in skeletal muscle. Therefore, the central hypothesis of this proposal is that degeneration and disorganization of smooth muscle cells in veins compromises the vessel wall structural integrity through (1) changes in lipoprotein metabolism that influence smooth muscle cell proliferation and (2) regulated protein degradation, causing smooth muscle proteolysis and remodeling. We propose to: 1) Characterize the changes seen in early venous disease, specifically, alterations in lipid metabolism related proteins, and determine their contribution to smooth muscle cell integrity; 2) Study the mechanisms that contribute to proteolysis-dependent smooth muscle cell changes and loss of structural integrity in varicose veins; and 3) Examine the relevance of lipoprotein metabolism and the ubiquitin-proteasome pathway in a long-term model of venous hypertension. In summary, this proposal wil l use a combination of molecular, histological, and in vivo studies to define the mechanism(s) that contribute to the development of varicose vein s and chronic venous insufficiency as well as establish models needed for the study of potential therapies. Although the development of venous disease is multifactorial, the pivotal processes responsible for triggering early disease as well as progression to chronic disease are unknown. This application will study an extremely common vascular disease that is not currently under investigation by any NIH-funded programs and will allow the applicant to utilize their fundamental interest in vascular biology, surgical research skills, and their clinical interest in the treatment of varicose veins.