Functional and structural correlates of PCSK9 association with lipoproteins
PCSK9 与脂蛋白关联的功能和结构相关性
基本信息
- 批准号:9335438
- 负责人:
- 金额:$ 53.38万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2016
- 资助国家:美国
- 起止时间:2016-09-01 至 2020-06-30
- 项目状态:已结题
- 来源:
- 关键词:ANGPTL3 geneAmino AcidsApolipoproteins BBindingBinding ProteinsBiological AssayBlocking AntibodiesCardiovascular systemCatalytic DomainCholesterolCleaved cellClinicalComplexDyslipidemiasEnzymesEpidermal Growth FactorEuropeEventHepatocyteHourInheritedInterruptionLDL Cholesterol LipoproteinsLaboratoriesLipoprotein (a)LipoproteinsLow Density Lipoprotein ReceptorLow-Density LipoproteinsMediatingMethodsMolecularMutationMyocardial InfarctionN-terminalPathway interactionsPhysiologicalPlasmaPlayProcessProductionPropertyProprotein ConvertasesProteinsRecyclingRegulationRestRoleRouteSubtilisinsSurfaceSyndromeTherapeuticTimeWorkbasecholesterol controlcholesterol traffickingclinically relevantcohortinhibitor/antagonistmutation carrierneutralizing antibodyparticlepreventreceptor bindingreceptor expressiontargeted treatmenttherapeutic targetuptake
项目摘要
Summary
Proprotein convertase subtilisin kexin type 9 (PCSK9) is a circulatory protein that binds to the low-density
lipoprotein receptor (LDLR), induces its degradation, and increases LDL-cholesterol (LDL-C) levels. Thus,
PCSK9 is a therapeutic target to increase LDLR expression and reduce plasma LDL-C levels, and PCSK9
inhibitors have recently been approved for use in the US and Europe. Plasma PCSK9 levels are highly
correlated to LDL-C levels, both because elevated PCSK9 levels increase plasma LDL levels by decreasing
LDLR and because up to 40% of plasma PCSK9 is physically associated with LDL, a discovery initially made in
our laboratory and later confirmed by others. Plasma PCSK9 is found in two main forms, an intact form (62
kDa) and a furin-cleaved form (55 kDa). We show that PCSK9 associated with LDL is mainly in the intact 62-
kDa form, whereas the rest of plasma PCSK9 is mainly as the 55 kDa furin-cleaved fragment. The intact, LDL-
associated PCSK9 seems to have an increased capacity to bind and degrade LDLR. Our preliminary results
also suggest that LDL protects PCSK9 from cleavage by furin. However, it is still unclear what drives the
compartmentalization of the molecular forms of circulating PCSK9, and whether there are functional correlates
to this compartmentalization. Thus, we propose studies to clarify the connection between plasma PCSK9
forms, molecular drivers of their lipoprotein association, and LDLR degradation activity. Moreover, we propose
to develop a high-throughput method to detect LDL-bound PCSK9 in plasma and to study PCSK9 association
with other apoB-containing lipoproteins, such as Lp(a), and with intracellular apoB. Finally, we will study the
mechanisms leading to the unexpectedly large time delay between the initial PCSK9-LDLR contact and the
eventual degradation of the LDLR, as this seems to be due to a complex intracellular routing of PCSK9 which
includes a re-secretion/recycling step. The central hypothesis of this proposal is that LDL carries a significant
portion of the intact plasma PCSK9 form (62 kDa), which may behave differently in LDLR binding and
degradation compared with the other major form of plasma PCSK9 (55 kDa). The results from these studies
will enhance our understanding of both the physiologic role of PCSK9 association with lipoproteins and the
mechanism by which PCSK9 inhibition produces therapeutic gains, and may inform alternative strategies to
inhibit the effect of PCSK9 on LDLR through interruption of PCSK9 association with lipoproteins.
.
总结
前蛋白转化酶枯草杆菌蛋白酶kexin 9型(PCSK 9)是一种循环蛋白,
脂蛋白受体(LDLR),诱导其降解,并增加LDL-胆固醇(LDL-C)水平。因此,在本发明中,
PCSK 9是增加LDLR表达和降低血浆LDL-C水平的治疗靶点,并且PCSK 9
抑制剂最近已在美国和欧洲被批准使用。血浆PCSK 9水平较高
与LDL-C水平相关,因为PCSK 9水平升高通过降低血浆LDL水平而增加血浆LDL水平。
因为高达40%的血浆PCSK 9与LDL物理相关,这一发现最初是在2008年发现的。
我们的实验室,后来被其他人证实。血浆PCSK 9主要以两种形式存在,一种是完整形式(62
kDa)和弗林蛋白酶切割的形式(55 kDa)。我们发现,与LDL相关的PCSK 9主要存在于完整的62-
血浆PCSK 9的其余部分主要是55 kDa弗林蛋白酶切割片段。完整的低密度脂蛋白-
相关的PCSK 9似乎具有增加的结合和降解LDLR的能力。我们的初步结果
也表明LDL保护PCSK 9免受弗林蛋白酶的切割。然而,目前还不清楚是什么驱动了
循环PCSK 9分子形式的区室化,以及是否存在功能相关性
这种划分。因此,我们提出研究,以澄清血浆PCSK 9
形式、其脂蛋白结合的分子驱动因素和LDLR降解活性。此外,我们建议
开发一种高通量方法来检测血浆中LDL结合的PCSK 9,并研究PCSK 9的相关性
与其他含apoB的脂蛋白,如Lp(a),以及与细胞内apoB。最后,我们将研究
导致初始PCSK 9-LDLR接触和PCSK 9-LDLR接触之间意外大的时间延迟的机制
LDLR的最终降解,因为这似乎是由于PCSK 9复杂的细胞内途径,
包括再分泌/再循环步骤。该建议的中心假设是LDL携带显著的
完整血浆PCSK 9形式的一部分(62 kDa),其在LDLR结合中可能表现不同,
与其他主要形式的血浆PCSK 9(55 kDa)相比,这些研究的结果
这将增强我们对PCSK 9与脂蛋白相关的生理作用以及
PCSK 9抑制产生治疗效果的机制,并可能为替代策略提供信息,
通过阻断PCSK 9与脂蛋白的结合,抑制PCSK 9对LDLR的作用。
.
项目成果
期刊论文数量(0)
专著数量(0)
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会议论文数量(0)
专利数量(0)
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{{ truncateString('SERGIO FAZIO', 18)}}的其他基金
Functional and structural correlates of PCSK9 association with lipoproteins
PCSK9 与脂蛋白关联的功能和结构相关性
- 批准号:
9155814 - 财政年份:2016
- 资助金额:
$ 53.38万 - 项目类别:
PCSK9, Lipoprotein receptors, and Atherosclerosis
PCSK9、脂蛋白受体和动脉粥样硬化
- 批准号:
8248701 - 财政年份:2011
- 资助金额:
$ 53.38万 - 项目类别:
PCSK9, Lipoprotein receptors, and Atherosclerosis
PCSK9、脂蛋白受体和动脉粥样硬化
- 批准号:
8606492 - 财政年份:2011
- 资助金额:
$ 53.38万 - 项目类别:
PCSK9, Lipoprotein receptors, and Atherosclerosis
PCSK9、脂蛋白受体和动脉粥样硬化
- 批准号:
8436303 - 财政年份:2011
- 资助金额:
$ 53.38万 - 项目类别:
PCSK9, Lipoprotein receptors, and Atherosclerosis
PCSK9、脂蛋白受体和动脉粥样硬化
- 批准号:
8131556 - 财政年份:2011
- 资助金额:
$ 53.38万 - 项目类别:
MACROPHAGE EXPRESSION OF APOAI AND ATHEROSCLEROSIS
APOAI 和动脉粥样硬化的巨噬细胞表达
- 批准号:
6191927 - 财政年份:2000
- 资助金额:
$ 53.38万 - 项目类别:
MACROPHAGE EXPRESSION OF APOAI AND ATHEROSCLEROSIS
APOAI 和动脉粥样硬化的巨噬细胞表达
- 批准号:
6390892 - 财政年份:2000
- 资助金额:
$ 53.38万 - 项目类别:
MACROPHAGE EXPRESSION OF APOAI AND ATHEROSCLEROSIS
APOAI 和动脉粥样硬化的巨噬细胞表达
- 批准号:
6760012 - 财政年份:2000
- 资助金额:
$ 53.38万 - 项目类别:
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