3OST1 Deficiency and Cardiovascular Disease

3OST1 缺乏与心血管疾病

• 批准号: 6870086
• 负责人: NICHOLAS W SHWORAK
• 金额: $ 25.5万
• 依托单位: DARTMOUTH COLLEGE
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-02-15 至 2009-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6870086
• 关键词: aging; aorta; clinical research; echocardiography; enzyme deficiency; enzyme induction /repression; gender difference; genetic models; genetically modified animals; heart function; heart valve disorder; hemodynamics; heparan sulfate; human subject; human tissue; hypertension; laboratory mouse; longitudinal human study; mitral valve; molecular pathology; sulfotransferase; vascular endothelium

DESCRIPTION (provided by applicant): Repair and replacement of the leaky mitral valve are common cardiac surgical operations that are most frequently necessitated by myxomatous degeneration of the mitral valve. This degenerative condition can additionally exhibit severe cardiovascular complications including heart arrhythmias, sudden death, stroke and heart failure in the elderly. Genetic analyses show that myxomatous degeneration can arise from defects in one of several genes; however, the major causative genes have yet to be identified. Inheritance of just a single gene is insufficient to predict the development of clinical disease. Thus, severe disease likely results from an interaction between multiple genes, ageing and physiology. At present, there is no animal system to evaluate such complex interactions. We have generated mice deficient for the Hs3stl gene (Hs3st1-/-) and its encoded enzyme, 3OST1. Aged Hs3st1-/- mice develop myxomatous degeneration in at least mitral and aortic valves. This animal provides a unique opportunity to evaluate how aging, genetic and physiologic factors interact and contribute to the development of myxomatous degenerative valve disease and it' deleterious cardiovascular sequelae. We propose to: (1) Establish the influence of aging, gender and 3OST1 deficiency on the myxomatous degeneration of individual heart valves and assess the cardiovascular consequences of heart valve dysfunction. This will be accomplished by evaluating Hs3stl +and wild-type littermate controls (Hs3st1 +/+) at defined age points for alterations in valve and cardiac structure and function. (2) Evaluate the interplay between aging, hypertension and 3OST1 deficiency on myxomatous valvular degeneration of heart valves. Surgical constriction of the aorta will be conducted on Hs3st1+ and Hs3stl +/+ mice to induce moderate hypertension. At defined age points, each heart valve and the heart will be examined for alterations in structure and function. (3) Test for involvement of 3OST1 in human myxomatous mitral valve prolapse. A pilot case control study will examine whether 3OST1 plasma levels are associated with this disease in general or with specific patient subcategories. Archival human valve tissues will also be examined to test for local tissue reductions in 3OST1 product. (4) Distinguish whether the protective effects of 3OST1 stem from its action within endothelial cells or from a systemic influences of plasma borne enzyme. Transgenic mice shall be generated to express secreted or nonsecreted forms of 3OST1+ selectively in vascular endothelial cells. Selective correction of disease in Hs3st1+ mice will reveal the critical site of action. Together these studies provide the foundations for elucidating the molecular basis of this valvular disease and will provide a rigorously characterized model for elucidating how severe myxomatous disease results from interactions between multiple causative genes, aging and physiology.

描述(由申请人提供)： 修复和替换漏水的二尖瓣是常见的心脏外科手术，最常见的是由于二尖瓣粘液瘤变性所致。这种退行性疾病还会表现出严重的心血管并发症，包括心律失常、猝死、中风和老年人的心力衰竭。遗传分析表明，粘液瘤退行性变可由几个基因中的一个缺陷引起；然而，主要致病基因尚未确定。只有一个基因的遗传不足以预测临床疾病的发展。因此，严重疾病很可能是多个基因、衰老和生理相互作用的结果。目前，还没有动物系统来评估这种复杂的相互作用。我们产生了缺乏Hs3stl基因(HS3ST1-/-)及其编码酶3OST1的小鼠。老年HS3ST1-/-小鼠至少在二尖瓣和主动脉瓣发生粘液瘤样变性。这种动物提供了一个独特的机会来评估衰老、遗传和生理因素如何相互作用并促进粘液瘤退行性瓣膜病及其有害的心血管后遗症的发展。我们建议：(1)建立年龄、性别和3OST1缺陷对个体心脏瓣膜粘液瘤样变性的影响，并评估心脏瓣膜功能不全的心血管后果。这将通过评估Hs3stl+和野生型对照(HS3ST1+/+)在特定年龄点的瓣膜和心脏结构和功能的变化来实现。(2)探讨增龄、高血压和3OST1缺乏对心脏瓣膜粘液瘤样变性的影响。手术缩窄HS3ST1+和Hs3st1+/+小鼠的主动脉以诱导中度高血压。在规定的年龄点，将检查每个心脏瓣膜和心脏的结构和功能的变化。(3)检测3OST1在粘液瘤型二尖瓣脱垂中的作用。一项试点病例对照研究将检查3OST1血浆水平是否与这种疾病总体或特定患者亚类相关。存档的人体瓣膜组织也将被检查，以测试3OST1产品中局部组织的减少。(4)区分3OST1的保护作用是来源于其在血管内皮细胞内的作用，还是来自于血浆酶的全身影响。应建立转基因小鼠，在血管内皮细胞中选择性表达分泌型或非分泌型3OST1+。对HS3ST1+小鼠的疾病进行选择性纠正将揭示作用的关键部位。总之，这些研究为阐明这种瓣膜疾病的分子基础提供了基础，并将为阐明多个致病基因、衰老和生理之间的相互作用如何导致严重的粘液瘤疾病提供一个严格表征的模型。