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，存在于多达30%的成年人中，显然与显著的发病率有关。尽管与这种综合征相关的发病率和显著的医疗费用很高，但旨在确定静脉曲张和慢性静脉功能不全的机制(S)的科学研究一直很少。在初步数据中，静脉疾病的进展与20多个通常与脂肪细胞去分化相关的脂蛋白相关基因的显著减少有关。骨骼肌中与泛素依赖的蛋白质降解有关的已知基因也增加了。因此，这一建议的中心假设是，静脉中平滑肌细胞的退化和破坏通过(1)影响血管细胞增殖的脂蛋白代谢的变化和(2)调节蛋白质降解，导致平滑肌蛋白分解和重塑，从而损害血管壁结构的完整性。我们建议：1)表征早期静脉疾病中可见的变化，特别是脂代谢相关蛋白的变化，并确定它们对血管细胞完整性的贡献；2)研究静脉曲张中依赖蛋白分解的平滑肌细胞变化和结构完整性丧失的机制；以及3)在静脉高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。综上所述，L将使用分子、组织学和体内研究相结合的方法来确定静脉曲张S和慢性静脉功能不全的发病机制(S)，并建立研究潜在治疗方法所需的模型。尽管静脉疾病的发展是多因素的，但导致早期疾病以及进展为慢性病的关键过程尚不清楚。这项申请将研究一种非常常见的血管疾病，目前NIH资助的任何项目都没有对这种疾病进行调查，并将允许申请者利用他们对血管生物学的基本兴趣、外科研究技能以及他们对静脉曲张治疗的临床兴趣。

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.