Structural basis for cardioprotective HDL
心脏保护性 HDL 的结构基础
基本信息
- 批准号:10308003
- 负责人:
- 金额:$ 69.12万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-12-15 至 2023-11-30
- 项目状态:已结题
- 来源:
- 关键词:ATP binding cassette transporter 1AdoptedAffectAgreementAnimal ModelAnimalsApolipoprotein A-IApolipoproteinsAtherosclerosisBindingBiochemicalC-terminalCardiovascular DiseasesCarotid Atherosclerotic DiseaseCell Surface ProteinsChemicalsCholesterolComplementComplement ActivationCrystallizationDataDiabetes MellitusDockingEngineeringEnzymesFaceFoam CellsGoalsHeart DiseasesHigh Density Lipoprotein CholesterolHigh Density LipoproteinsHumanHuman bodyImpairmentIn VitroInnate Immune SystemInvestigationIsotope LabelingLeftLesionLipaseLipidsLiverLow Density Lipoprotein ReceptorMass Spectrum AnalysisMediatingMolecularMusMutateN-terminalPathway interactionsPatientsPharmaceutical PreparationsPhosphatidylcholine-Sterol O-AcyltransferasePhysiologicalPlasmaPropertyProtein FamilyProteinsReactionRegulation of ProteolysisResearchResolutionSodium ChlorideStructureTechniquesTestingType 2 diabeticadeno-associated viral vectoratherogenesiscardioprotectioncardiovascular disorder riskcell typeconformercrosslinkdiabeticdiabetic patientdimerheart disease riskin vivoinsightmacrophagemolecular modelingmonomermouse modelnon-diabeticparticlereconstitutionreplication factor Cscaffoldsimulationtargeted treatmenttherapy development
项目摘要
Our long-term goal is to establish the structural features responsible for the cardioprotective functions of HDL
in humans, which may have important implications for predicting CVD risk and developing HDL-targeted
therapeutics. We have recently shown that apolipoprotein A1 (APOA1), HDL’s major apolipoprotein, can
assume three different antiparallel isomeric structures we term rotamers. Strong preliminary data suggests that
the different rotamers exist in humans, and that they affect HDL size and ability to bind different proteins, and
have different abilities to promote cholesterol efflux from macrophages by the ABCA1 pathway. To determine
the physiological relevance of the APOA1 rotamers, we therefore propose two specific aims.
First, we will engineer Apoa1-/- mice to express mutated forms of human APOA1 that cause HDL to selectively
form specific rotamers of APOA1 in vivo. We will then determine the impact of the different rotamers on HDL
cholesterol efflux capacity, HDL size, HDL protein cargo, and atherosclerosis in LDL receptor-deficient mouse
models.
Second, we will complement our animal studies with analyses of HDLs of humans with and without carotid
atherosclerotic disease, and with and without diabetes. We will determine whether the distribution of specific
rotamers, HDL subspecies, and HDL protein cargo associate with cholesterol efflux capacity and whether they
associate with or predict atherosclerotic disease in these subjects. Because preliminary studies show that HDL
of diabetic patients have impaired cholesterol efflux capacity, and diabetic patients are at greatly increased risk
of cardiovascular disease, our proposed investigation of the structural features of HDL that associate with both
impaired HDL function and atherosclerotic disease could provide important insights into HDL-associated
factors that are cardioprotective but are independent of HDL cholesterol levels.
我们的长期目标是建立负责 HDL 心脏保护功能的结构特征
在人类中,这可能对预测 CVD 风险和开发 HDL 靶向具有重要意义
疗法。我们最近表明,HDL 的主要载脂蛋白载脂蛋白 A1 (APOA1) 可以
假设三种不同的反平行异构体结构,我们称之为旋转异构体。强有力的初步数据表明
人类体内存在不同的旋转异构体,它们会影响 HDL 的大小和结合不同蛋白质的能力,并且
具有通过 ABCA1 途径促进巨噬细胞胆固醇流出的不同能力。确定
鉴于 APOA1 旋转异构体的生理相关性,我们因此提出了两个具体目标。
首先,我们将改造 Apoa1-/- 小鼠,使其表达人类 APOA1 的突变形式,从而导致 HDL 选择性地
在体内形成 APOA1 的特异性旋转异构体。然后我们将确定不同旋转异构体对 HDL 的影响
LDL受体缺陷小鼠的胆固醇流出能力、HDL大小、HDL蛋白货物和动脉粥样硬化
模型。
其次,我们将通过分析有或没有颈动脉的人类 HDL 来补充我们的动物研究
动脉粥样硬化疾病,以及患有或不患有糖尿病。我们将确定是否分配具体的
旋转异构体、HDL 亚种和 HDL 蛋白货物与胆固醇流出能力相关,以及它们是否
与这些受试者的动脉粥样硬化疾病相关或预测。因为初步研究表明HDL
糖尿病患者的胆固醇流出能力受损,糖尿病患者的风险大大增加
心血管疾病的研究中,我们提出了对与心血管疾病相关的 HDL 结构特征的研究
HDL 功能受损和动脉粥样硬化疾病可以为 HDL 相关性提供重要见解
具有心脏保护作用但与高密度脂蛋白胆固醇水平无关的因素。
项目成果
期刊论文数量(0)
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会议论文数量(0)
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Karin E. Bornfeldt其他文献
Lecithin:cholesterol acyltransferase binds a discontinuous binding site on adjacent apolipoprotein A-I belts in HDL
卵磷脂:胆固醇酰基转移酶结合高密度脂蛋白中相邻载脂蛋白A - I条带上的不连续结合位点
- DOI:
10.1016/j.jlr.2025.100786 - 发表时间:
2025-05-01 - 期刊:
- 影响因子:4.100
- 作者:
Bethany Coleman;Shimpi Bedi;John H. Hill;Jamie Morris;Kelly A. Manthei;Rachel C. Hart;Yi He;Amy S. Shah;W. Gray Jerome;Tomas Vaisar;Karin E. Bornfeldt;Hyun Song;Jere P. Segrest;Jay W. Heinecke;Stephen G. Aller;John J.G. Tesmer;W. Sean Davidson - 通讯作者:
W. Sean Davidson
Effect of insulin-like growth factor I infusion on renal hypertrophy in experimental diabetes niellitus in rats
胰岛素样生长因子I输注对实验性糖尿病大鼠肾肥大的影响
- DOI:
10.1007/bf00401516 - 发表时间:
1991 - 期刊:
- 影响因子:8.2
- 作者:
Allan Flyvbjerg;Karin E. Bornfeldt;Hans Ørskov;Hans J. Arnqvist - 通讯作者:
Hans J. Arnqvist
APOA2 increases cholesterol efflux capacity to plasma HDL by displacing the C-terminus of resident APOA1
- DOI:
10.1016/j.jlr.2024.100686 - 发表时间:
2024-12-01 - 期刊:
- 影响因子:
- 作者:
Snigdha Sarkar;Jamie Morris;Youngki You;Hannah Sexmith;Scott E. Street;Stephanie M. Thibert;Isaac K. Attah;Chelsea M. Hutchinson Bunch;Irina V. Novikova;James E. Evans;Amy S. Shah;Scott M. Gordon;Jere P. Segrest;Karin E. Bornfeldt;Tomas Vaisar;Jay W. Heinecke;W. Sean Davidson;John T. Melchior - 通讯作者:
John T. Melchior
Binding and biological effects of insulin, insulin analogues and insulin-like growth factors in rat aortic smooth muscle cells. Comparison of maximal growth promoting activities
胰岛素、胰岛素类似物和胰岛素样生长因子在大鼠主动脉平滑肌细胞中的结合和生物效应。
- DOI:
- 发表时间:
1991 - 期刊:
- 影响因子:8.2
- 作者:
Karin E. Bornfeldt;R. A. Gidlöf;Å. Wasteson;M. Lake;A. Skottner;Hans J Arnqvist - 通讯作者:
Hans J Arnqvist
Apolipoprotein C3 induces inflammasome activation only in its delipidated form
载脂蛋白 C3 仅在其去脂形式下诱导炎性小体激活
- DOI:
10.1038/s41590-023-01423-2 - 发表时间:
2023-02-13 - 期刊:
- 影响因子:27.600
- 作者:
Cheng-Chieh Hsu;Baohai Shao;Jenny E. Kanter;Yi He;Tomas Vaisar;Joseph L. Witztum;Janet Snell-Bergeon;Gregory McInnes;Shannon Bruse;Omri Gottesman;Adam E. Mullick;Karin E. Bornfeldt - 通讯作者:
Karin E. Bornfeldt
Karin E. Bornfeldt的其他文献
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{{ truncateString('Karin E. Bornfeldt', 18)}}的其他基金
Triglycerides, Diabetes and Cardiovascular Disease
甘油三酯、糖尿病和心血管疾病
- 批准号:
10450856 - 财政年份:2020
- 资助金额:
$ 69.12万 - 项目类别:
Identifying new strategies for prevention of cardiovascular complications of diabetes
确定预防糖尿病心血管并发症的新策略
- 批准号:
10591588 - 财政年份:2020
- 资助金额:
$ 69.12万 - 项目类别:
Identifying new strategies for prevention of cardiovascular complications of diabetes
确定预防糖尿病心血管并发症的新策略
- 批准号:
10395427 - 财政年份:2020
- 资助金额:
$ 69.12万 - 项目类别:
Project 1. Diabetes, triglyceride-rich lipoproteins, and advanced atherosclerosis
项目1. 糖尿病、富含甘油三酯的脂蛋白和晚期动脉粥样硬化
- 批准号:
10450861 - 财政年份:2020
- 资助金额:
$ 69.12万 - 项目类别:
Triglycerides, Diabetes and Cardiovascular Disease
甘油三酯、糖尿病和心血管疾病
- 批准号:
10642739 - 财政年份:2020
- 资助金额:
$ 69.12万 - 项目类别:
Identifying new strategies for prevention of cardiovascular complications of diabetes
确定预防糖尿病心血管并发症的新策略
- 批准号:
9893203 - 财政年份:2020
- 资助金额:
$ 69.12万 - 项目类别:
Project 1. Diabetes, triglyceride-rich lipoproteins, and advanced atherosclerosis
项目1. 糖尿病、富含甘油三酯的脂蛋白和晚期动脉粥样硬化
- 批准号:
10642745 - 财政年份:2020
- 资助金额:
$ 69.12万 - 项目类别:
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