Defining the Role of Lipoprotein(a) and its Oxidized Phospholipids in the Development and Progression of Calcific Aortic Valve Disease Using Unique Transgenic Mouse Models

项目概要/摘要： 这个K08指导医生科学家奖的建议，旨在促进我的发展成为一个 研究钙化性主动脉瓣疾病（CAVD）的独立研究者。常见于老年人， 随着人口老龄化，预计到2030年，CAVD将影响全球450万人。CAVD是一个渐进的 主动脉瓣（AV）变得越来越增厚和钙化，最终导致严重的 AV狭窄、症状、左心室压力超负荷导致心力衰竭和死亡。常规 严重CAVD的治疗是经导管或外科AV置换术（AVR）。作为一名心脏病专家，我 我已经照顾了太多不符合这些程序的病人，以及那些患有 围手术期并发症，如中风，并了解预防性治疗的必要性。不幸的是， 目前还不存在预防CAVD发展或进展的有效药物疗法， 在这一竞技场的临床试验未能解决因果风险因素。最近，多种人类流行病学和 遗传和体外研究表明，脂蛋白（a）[Lp（a）]，氧化型脂蛋白的主要脂蛋白载体， 磷脂（OxPL）作为CAVD的危险因素。而Lp（a）水平升高，存在于35%的个体中， CAVD并不代表一个普遍的风险因素，它确定了结局不良风险最高的患者 以及如果确定Lp（a）和/或OxPL为致病因素，则可能受益于针对Lp（a）和/或OxPL的靶向治疗的患者 危险因素本课题的研究目标是：1）验证Lp（a）及其OxPL含量与脂蛋白（a）的关系， 导致体内CAVD的发生和进展; 2）确定Lp（a）和 OxPL在体内介导CAVD。在前期工作中，我建立了表达Lp（a）的转基因小鼠模型， 结合OxPL的突变型Lp（a），缺乏OxPL结合的突变型Lp（a），以及与结合OxPL的天然抗体组合的Lp（a）， 并中和OxPL，这是唯一可在我们的实验室，并将用于本提案。的 K08将建立在我的背景，作为一个心脏病专家和基础科学家在脂质代谢提供 以下培训目标：1）获得分子成像的独立技能，以研究AV钙化， CAVD进展的致病过程，使用小鼠模型，2）发展超声心动图的专业知识 评估AV血流动力学，临床上用于监测小鼠CAVD的进展，3）获得专业知识 在AV的蛋白质组学分析，以了解参与CAVD的途径，和4）获得的知识和技能 我需要通过我的多学科导师团队的指导，成为一名成功的独立调查员 包括Sotirios（Sam）Tsimikas博士，Joseph Witztum，Elena Aikawa和Kirk Peterson，以及仔细 精选课程到这个奖项结束时，我希望不仅获得了宝贵的洞察力， AV钙化进展的潜在机制，但也获得了专业知识和初步数据 需要竞争R01资金，并将这些知识转化为CAVD的新医学疗法。

Project Summary/Abstract: This K08 mentored physician-scientist award proposal has been designed to facilitate my development into an independent investigator studying calcific aortic valve disease (CAVD). Common in the elderly, and with our aging population, CAVD is expected to affect 4.5 million individuals globally by 2030. CAVD is a progressive disease in which the aortic valves (AV) become increasingly thickened and calcified, ultimately leading to severe AV narrowing, symptoms, left ventricular pressure overload leading to heart failure, and death. Conventional treatment for severe CAVD is transcatheter or surgical AV replacement (AVR). However, as a cardiologist, I have cared for too many patients who were ineligible for these procedures as well as those who suffered from peri-procedural complications such as stroke, and understand the need for preventative therapies. Unfortunately, effective medical therapies preventing the development or progression of CAVD do not currently exist, due to a failure of clinical trials in this arena to address causal risk factors. Recently, multiple human epidemiologic and genetic, as well as in vitro studies, have implicated lipoprotein(a) [Lp(a)], the major lipoprotein carrier of oxidized phospholipids (OxPL) as a risk factor for CAVD. While elevated Lp(a) levels, present in 35% of individuals with CAVD, does not represent a universal risk factor, it identifies patients who are at highest risk for poor outcomes and who may benefit from targeted therapies against Lp(a) and/or OxPL if these are determined to be causal risk factors. The research goals of this proposal are to: 1) test the hypothesis that Lp(a) and its OxPL content cause the development and progression of CAVD in vivo and 2) define the mechanisms by which Lp(a) and OxPL mediate CAVD in vivo. In preliminary work, I have established transgenic mouse models expressing Lp(a) that binds OxPL, mutant Lp(a) lacking OxPL binding, and Lp(a) in combination with a natural antibody that binds and neutralizes OxPL, which are uniquely available only in our laboratory and will be used for this proposal. The K08 will build upon my background as a cardiologist and a basic scientist in lipid metabolism by providing the following training objectives: 1) acquire independent skills in molecular imaging to study AV calcification, a central pathogenic process in progression of CAVD, using mouse models, 2) develop expertise in echocardiographic assessment of AV hemodynamics, used clinically to monitor progression of CAVD, in mice, 3) acquire expertise in proteomic analysis of AVs to understand pathways involved in CAVD, and 4) gain the knowledge and skills needed to be a successful independent investigator through guidance from my multidisciplinary mentorship team including Drs. Sotirios (Sam) Tsimikas, Joseph Witztum, Elena Aikawa, and Kirk Peterson, as well as carefully selected coursework. By the end of this award period, I expect to not only have gained invaluable insight into the mechanisms underlying the progression of AV calcification, but also acquired expertise and preliminary data needed to compete for R01 funding and to translate this knowledge into novel medical therapies for CAVD.