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

使用独特的转基因小鼠模型确定脂蛋白（a）及其氧化磷脂在钙化性主动脉瓣疾病的发生和进展中的作用

• 批准号: 10376739
• 负责人: Calvin Yeang
• 金额: $ 17.76万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-02-17 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10376739
• 关键词: Address; Affect; Aging; Apolipoproteins A; Apolipoproteins B; Award; Binding; Binding Sites; Blood Vessels; Caring; Cessation of life; Characteristics; Cholesterol; Clinical; Clinical Trials; Data; Development; Diet; Disease; Echocardiography; Elderly; Epidemiology; Failure; Funding; Genetic; Genetic study; Goals; Heart failure; Histologic; Human; In Vitro; Incidence; Individual; Inflammatory; Knowledge; Laboratories; Left; Lipids; Lipoprotein (a); Lipoproteins; Lysine; Measurement; Mediating; Mediator of activation protein; Medical; Mentors; Mentorship; Minerals; Molecular; Monitor; Morbidity - disease rate; Mus; Mutation; Operative Surgical Procedures; Outcome; Oxides; Pathogenicity; Pathway interactions; Patients; Phospholipids; Phosphorylcholine; Physicians; Physiologic intraventricular pressure; Population; Prevention therapy; Preventive therapy; Procedures; Process; Progressive Disease; Proteins; Proteomics; Randomized Clinical Trials; Research; Research Personnel; Risk; Risk Factors; Role; Scientist; Stroke; Symptoms; Techniques; Testing; Tissues; Training; Transgenic Mice; Transgenic Organisms; Translating; Variant; Work; aging population; aortic valve; aortic valve disorder; aortic valve replacement; apolipoprotein B-100; apolipoprotein Lp(a+); calcification; career; clinically relevant; comparative; conventional therapy; design; disorder risk; efficacy testing; epidemiology study; hemodynamics; high risk; human disease; in vivo; in vivo Model; insight; interstitial cell; lipid metabolism; lipidomics; liquid chromatography mass spectrometry; molecular imaging; mouse model; multidisciplinary; mutant; natural antibodies; novel; novel therapeutics; osteogenic; prevent; skills; targeted treatment; valve replacement

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.

项目摘要/摘要： 这份K08指导医生-科学家奖提案旨在促进我发展成为一名 研究钙化性主动脉瓣病(CAVD)的独立研究员。在老年人中很常见，在我们的 随着人口老龄化，预计到2030年，全球将有450万人受到CAVD的影响。CAVD是一种进步 主动脉瓣(AV)变得越来越厚和钙化，最终导致严重的 房室狭窄、症状、左心室压力超负荷导致心力衰竭和死亡。传统型 严重CAVD的治疗方法是经导管或外科房室置换术(AVR)。然而，作为一名心脏病专家，我 我照顾了太多不符合这些手术条件的患者以及那些遭受 了解中风等围手术期并发症，并了解预防性治疗的必要性。不幸的是， 目前尚不存在预防CAVD发展或进展的有效医学疗法，原因是 这一领域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 遗传和体外研究都表明，脂蛋白(A)[Lp(A)]是氧化的主要脂蛋白载体 磷脂(OxPL)是CAVD的危险因素。而Lp(A)水平升高，出现在35%的 CAVD并不代表普遍的风险因素，它确定了预后不良的风险最高的患者 谁可以从针对Lp(A)和/或OxPL的靶向治疗中受益，如果这些被确定为原因的话 风险因素。这一建议的研究目标是：1)检验Lp(A)及其OxPL含量的假设 导致体内CAVD的发生和发展以及2)确定Lp(A)和Lp(A)和Lp(A)的机制 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。 它结合OxPL、缺乏OxPL结合的突变体Lp(A)和Lp(A)与结合的天然抗体相结合 并中和了OxPL，这是只有我们实验室才有的，将用于本提案。这个 K08将在我作为心脏病专家和脂类代谢基础科学家的基础上提供 以下培训目标：1)掌握分子成像方面的独立技能，以研究房室钙化， 利用小鼠模型研究CAVD进展的发病过程，2)发展超声心动图专业知识 评估心动过速血流动力学，临床上用于监测小鼠的CAVD进展，3)获得专业知识 在AVs的蛋白质组学分析中，了解参与CAVD的途径，以及4)获得知识和技能 我需要在我的多学科指导团队的指导下成为一名成功的独立调查员 包括Sotirios(Sam)Tsimikas博士、Joseph Witztom博士、Elena Aikawa博士和Kirk Peterson博士，以及谨慎地 精选课程作业。到这个颁奖期结束时，我希望不仅获得对 房室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，并将这一知识转化为CAVD的新医学疗法。