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，存在于高达30%的成人人群中，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费用，但一直缺乏旨在确定导致静脉曲张和慢性静脉功能不全的机制的科学研究。在初步数据中，静脉疾病的进展与20多种脂蛋白相关基因的显著减少有关，这些基因通常与脂肪细胞去分化有关。骨骼肌中参与泛素依赖蛋白降解的基因也有所增加。因此，本研究的中心假设是，静脉平滑肌细胞的变性和解体通过(1)影响平滑肌细胞增殖的脂蛋白代谢改变和(2)调节蛋白质降解，导致平滑肌蛋白水解和重塑，从而损害血管壁结构完整性。我们建议：1)描述早期静脉疾病中所见的变化，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)研究导致静脉曲张蛋白水解依赖性平滑肌细胞改变和结构完整性丧失的机制；3)在静脉高血压长期模型中检测脂蛋白代谢和泛素-蛋白酶体途径的相关性。总之，本提案将结合分子、组织学和体内研究来确定导致静脉曲张和慢性静脉功能不全的机制，并建立研究潜在治疗方法所需的模型。虽然静脉疾病的发展是多因素的，但引发早期疾病以及发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，目前没有任何美国国立卫生研究院资助的项目进行研究，并允许申请人利用他们在血管生物学、外科研究技能和静脉曲张治疗方面的基本兴趣。

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.