3OST1 Deficiency and Cardiovascular Disease

描述（由申请人提供）： 二尖瓣渗漏的修复和置换是常见的心脏外科手术，最常见的是二尖瓣粘液瘤变性。这种退行性疾病还可能表现出严重的心血管并发症，包括老年人的心律失常、猝死、中风和心力衰竭。遗传分析表明，粘液瘤变性可能是由几个基因之一的缺陷引起的;然而，主要的致病基因尚未确定。仅单个基因的遗传不足以预测临床疾病的发展。因此，严重的疾病可能是多个基因、衰老和生理之间相互作用的结果。目前，还没有动物系统来评估这种复杂的相互作用。我们已经产生了Hs 3st 1基因（Hs 3st 1-/-）及其编码的酶，3 OST 1缺陷的小鼠。老年Hs 3st 1-/-小鼠至少在二尖瓣和主动脉瓣中发生粘液瘤变性。这种动物提供了一个独特的机会，以评估衰老，遗传和生理因素如何相互作用，并有助于粘液瘤性退行性瓣膜病的发展及其有害的心血管后遗症。我们建议：（1）确定年龄、性别和3 OST 1缺乏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障碍的心血管后果。这将通过在规定的年龄点评价Hs 3st 1+和野生型同窝对照（Hs 3st 1 +/+）的瓣膜和心脏结构和功能变化来实现。(2)评估衰老、高血压和3 OST 1缺陷对心脏瓣膜粘液瘤性瓣膜变性的相互作用。将对Hs 3st 1+和Hs 3stl +/+小鼠进行主动脉的手术缩窄，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变化。(3)检测3 OST 1与人类粘液瘤性二尖瓣脱垂的关系一项初步病例对照研究将检查3 OST 1血浆水平是否与一般疾病或特定患者亚类相关。还将检查存档的人体瓣膜组织，以测试3 OST 1产品的局部组织减少情况。(4)区分3 OST 1的保护作用是源于其在内皮细胞内的作用还是源于血浆携带的酶的全身影响。应生成转基因小鼠，以在血管内皮细胞中选择性表达分泌或非分泌形式的3 OST 1+。Hs 3st 1+小鼠疾病的选择性纠正将揭示关键作用部位。这些研究为阐明这种瓣膜病的分子基础提供了基础，并将为阐明多个致病基因、衰老和生理学之间的相互作用如何导致严重的粘液瘤病提供严格表征的模型。

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.