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： 这项K08指导的医师科学家奖奖旨在促进我的发展 独立研究者研究钙化主动脉瓣疾病（CAVD）。在老年人和我们的 人口老龄化，CAVD预计到2030年将影响全球450万个人。CAVD是一个进步 主动脉瓣（AV）变得越来越增厚和钙化的疾病，最终导致严重 AV狭窄，症状，左心室压力超负荷导致心力衰竭和死亡。传统的 严重CAVD的治疗是经导管或手术AV置换（AVR）。但是，作为心脏病学家，我 已经照顾了太多没有资格的患者，以及那些患有这些程序的患者 旁边的并发症（例如中风），并了解预防疗法的需求。很遗憾， 由于目前不存在防止CAVD发展或进展的有效医疗疗法，因此 该领域的临床试验未能解决因果风险因素。最近，多个人类流行病学和 遗传以及体外研究都暗示了脂蛋白（a）[LP（a）]，这是主要的氧化脂蛋白载体 磷脂（OXPL）是CAVD的危险因素。虽然LP（a）级别升高，但有35％的人 CAVD，并不代表普遍的危险因素，它确定了最不良预后风险的患者 如果确定为因果关系 风险因素。该提案的研究目标是：1）检验LP（A）及其OXPL含量的假设 导致CAVD在体内的发展和进展和2）定义LP（a）和 OXPL在体内介导Cavd。在初步工作中，我已经建立了表达LP（a）的转基因小鼠模型 结合OXPL，突变体LP（A）缺乏OXPL结合，LP（A）与结合的天然抗体结合 并中和OXPL，仅在我们的实验室中独特可用，并将用于该建议。这 K08将以我作为心脏病专家和脂质代谢的基础科学家的背景为基础 以下培训目标：1）获得分子成像中的独立技能来研究AV钙化，这是一个中央 使用小鼠模型的CAVD进展过程中的致病过程，2）在超声心动图中发展专业知识 评估AV血液动力学，用于监测CAVD进展的AV血液动力学，3）获取专业知识 在对AV的蛋白质组学分析中了解CAVD涉及的途径，以及4）获得知识和技能 需要通过我的多学科指导团队的指导成为成功的独立研究者 包括Drs。 Sotirios（Sam）Tsimikas，Joseph Witztum，Elena Aikawa和Kirk Peterson，以及仔细的 选定的课程。到这个奖励期结束时，我不仅希望获得无价的见解 AV钙化进展的基础机制，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的新医疗疗法。