PCSK9: Genetic Variation and Molecular Action

PCSK9：遗传变异和分子作用

• 批准号: 8686026
• 负责人: JAY D. HORTON
• 金额: $ 42.41万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8686026
• 关键词: Cardiovascular system; Cause of Death; Cholesterol Homeostasis; Clinical; Development; Disease; Event; Funding; Genetic Variation; Grant; Hepatocyte; Human; Hyperactive behavior; In Vitro; Individual; Liver; Low-Density Lipoproteins; Mediating; Metabolism; Molecular; Mutation; Plasma; Prevention; Preventive; Proprotein Convertases; Proteins; Risk Factors; Role; Small Interfering RNA; Subtilisins; Transgenic Mice; United States; base; cardiovascular risk factor; expression cloning; hypercholesterolemia; in vivo; kexin; loss of function mutation; mutant

Despite significant advances in preventive therapies, CHD remains the leading cause of death in the United States. An elevated level of plasma LDL-C is the single most important risk factor for the development of this disease (16), and LDL-lowering forms the cornerstone of CHD prevention. During the last decade, PCSK9 (proprotein convertase subtilisin/kexin type 9) has emerged as a potent regulator of LDLR levels in liver, and thus of plasma LDL-C concentrations (17). We have shown that haploinsufficiency of PCSK9 due to loss-of-function mutations (18) is associated with a 28% reduction in plasma levels of LDL-C and an 88% reduction in cardiovascular events (2). The most compelling evidence of the importance of PCSK9 in plasma LDL-C metabolism is the finding that individuals with no circulating PCSK9 have exceedingly low plasma levels of LDL-C (-15 mg/dL) (19). To date, no adverse clinical sequela has been found in humans lacking PCSK9. These observations, which were made during the last funding period of this grant, established that blocking the action of PCSK9 is a viable and potent target for the treatment of hypercholesterolemia and the reduction of cardiovascular risk. As such, a complete characterization of the molecular mechanisms by which PCSK9 functions to degrade LDLRs is paramount.

尽管预防疗法取得了重大进展，但CHD仍然是领先的 美国死亡原因。血浆LDL-C水平升高是最重要的危险因素 为了发育这种疾病（16），降低LDL构成了CHD预防的基石。期间 在过去的十年 肝脏中的LDLR水平，因此等离子体LDL-C浓度（17）。我们已经证明 由于功能丧失突变（18）引起的PCSK9与血浆LDL-C水平降低28％有关 心血管事件减少了88％（2）。最令人信服的证据表明PCSK9的重要性 在血浆LDL-C代谢中，没有循环PCSK9的个体非常低 LDL-C（-15 mg/dl）的血浆水平（19）。迄今为止，在人类中尚未发现不良的临床后遗症 缺少PCSK9。这些观察结果是在本赠款的最后资助期间提出的 阻止PCSK9的作用是治疗高胆固醇血症和 降低心血管风险。因此，通过 哪些PCSK9功能降解LDLR是至关重要的。