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
基本信息
- 批准号:10450861
- 负责人:
- 金额:$ 40.47万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-08-15 至 2025-07-31
- 项目状态:未结题
- 来源:
- 关键词:ANGPTL3 geneAddressAffectAntisense OligonucleotidesApolipoproteinsArterial Fatty StreakAtherosclerosisCREB1 geneCardiovascular DiseasesCaspaseCessation of lifeCholesterolComplementCyclic AMP-Responsive DNA-Binding ProteinDataDiabetes MellitusDiabetic mouseEventExhibitsHealthHemorrhageHepaticHumanHuman GeneticsHypertriglyceridemiaInflammasomeInsulin ReceptorInsulin ResistanceInsulin deficiencyInsulin-Dependent Diabetes MellitusLDL Cholesterol LipoproteinsLesionLesion by MorphologyLinkLipidsLipoproteinsMediatingMetabolic syndromeMetabolismModelingMusMutationMyeloid CellsNecrosisNon-Insulin-Dependent Diabetes MellitusPathway interactionsPatientsPhenotypePlasmaPrediabetes syndromePrevention strategyProteinsPublishingReceptor SignalingResidual stateRisk FactorsRoleSerumSeveritiesTestingTimeTriglyceride MetabolismTriglyceridesatherosclerosis riskcardiovascular disorder riskdiabeticdiabetic patientin vivoinsightinterestloss of function mutationmacrophagemouse modelnon-diabeticnovelnovel strategiesparticlepreventtraittranscription factortreatment effecttreatment strategyuptake
项目摘要
Both type 1 diabetes mellitus (T1DM), type 2 diabetes mellitus (T2DM) and metabolic syndrome (MetS; also
known as pre-diabetes) increase the risk of atherosclerosis, the leading cause of cardiovascular disease (CVD)
events and death in diabetic patients. Even with statin treatment to effectively lower LDL cholesterol, diabetes
is associated with increased CVD risk linked to abnormal metabolism of triglyceride-rich lipoproteins (TRLs)
and their remnant lipoprotein particles (RLPs). Novel strategies to enhance TRL clearance have therefore
recently generated significant interest, especially in the setting of diabetes. This application uses three
strategies to increase TRL and RLP clearance in diabetes; i) inhibition of apolipoprotein C3 (APOC3), ii)
inhibition of angiopoietin-like 3 (ANGPTL3), and iii) hepatic expression of an active form of the transcription
factor CREB-H (cAMP response element-binding protein H). The proposed studies build on strong preliminary
data demonstrating that diabetes accelerates progression of advanced lesions and that normalizing circulating
levels of TRLs prevents atherosclerosis in diabetic mice. Furthermore, diabetes causes increased macrophage
death associated with accumulation of cellular cholesterol and caspase 11 activation, which we hypothesize
contributes to the more advanced atherosclerotic lesion phenotype. Collectively, our observations support the
following hypothesis: Diabetes accelerates advanced atherosclerosis by increasing APOC3 and
associated TRLs and RLPs, which in turn induce macrophage lipid loading and exacerbate the death of
macrophages by pyroptosis. Such a mechanism could help explain the increased CVD risk in subjects with
diabetes. The first specific aim will address whether APOC3-enriched TRLs/RLPs are required for diabetes-
mediated atherosclerosis progression. We propose to test this hypothesis and to clarify the role of APOC3 by
normalizing plasma APOC3 and/or TRL/RLP levels in mouse models of T1DM and MetS/T2DM by three
distinct approaches; the use of an Apoc3 antisense oligonucleotide (ASO), an Angptl3 ASO, which reduces
TRLs and other lipoproteins independent of hepatic Apoc3 expression, and hepatic expression of CREB-H,
which lowers TRLs without affecting total plasma levels of APOC3. Contrasting the effects of these treatments
will provide new insights into the role of APOC3 versus TRL/RLP lowering. The second specific aim will
determine whether pyroptosis mediated by APOC3-enriched TRLs/RLPs contributes to lesional macrophage
death and advanced lesions in diabetes. We propose to mechanistically test the importance of this pathway by
using mice deficient in caspase 11 and gasdermin D, its downstream effector, in myeloid cells. We also expect
that pyroptosis will be prevented by TRL-lowering in diabetic mice. The in vivo studies will be complemented by
mechanistic studies in macrophages to clarify the pathways responsible in diabetes-induced macrophage
death, and by studies addressing mechanisms whereby reduced insulin receptor signalling leads to increased
levels of APOC3 in models of T1DM and MetS/T2DM.
1型糖尿病(T1 DM)、2型糖尿病(T2 DM)和代谢综合征(METS;还
糖尿病前期)增加动脉粥样硬化的风险,动脉粥样硬化是心血管疾病(CVD)的主要原因
糖尿病患者的事件和死亡。即使他汀类药物能有效降低低密度脂蛋白胆固醇,糖尿病
与富含甘油三酯的脂蛋白(TRL)代谢异常有关的心血管风险增加有关
和他们的残余脂蛋白颗粒(RLP)。因此,加强TRL通关的新战略
最近引起了人们的极大兴趣,特别是在糖尿病的背景下。此应用程序使用三个
提高糖尿病患者TRL和RLP清除的策略:i)抑制载脂蛋白C3(Apoc3),ii)
抑制血管生成素样3(Angptl3),以及III)转录的活性形式在肝脏中的表达
因子CREB-H(cAMP反应元件结合蛋白H)。拟议的研究建立在强大的初步基础上
数据显示,糖尿病加速晚期病变的进展,并使循环正常化
TRLS水平可预防糖尿病小鼠的动脉粥样硬化。此外,糖尿病还会导致巨噬细胞增多。
死亡与细胞胆固醇积累和caspase 11激活有关,我们假设这一点
有助于更高级的动脉粥样硬化病变表型。总的来说,我们的观察结果支持
以下假设:糖尿病通过增加APOC3和APOC3而加速晚期动脉粥样硬化
相关的TRL和RLP,进而诱导巨噬细胞脂质负荷,并加剧死亡
巨噬细胞由下垂引起。这样的机制可以帮助解释心血管疾病风险增加的原因
糖尿病。第一个具体目标将解决糖尿病是否需要富含APOC3的TRL/RLP-
介导动脉粥样硬化的进展。我们建议检验这一假说,并通过以下方式阐明APOC3的作用
使T1 DM和Mets/T2 DM小鼠模型血浆APOC3和/或TRL/RLP水平正常化
不同的方法;使用APOC3反义寡核苷酸(ASO),Angptl3 ASO,它减少了
TRLS和其他脂蛋白不依赖于肝脏APOC3的表达和CREB-H的肝脏表达,
这降低了TRL,而不影响血浆总APOC3水平。对比这些治疗方法的效果
将为APOC3与TRL/RLP降低的作用提供新的见解。第二个具体目标是
确定APOC3富集型TRLS/RLPs介导的下垂是否对损伤性巨噬细胞有贡献
糖尿病的死亡和晚期病变。我们建议通过以下方式机械地测试这一途径的重要性
使用在髓系细胞中缺乏caspase 11及其下游效应因子Gasdermin D的小鼠。我们也期待着
通过降低糖尿病小鼠的TRL,可以预防这种下垂。体内研究将得到以下补充
巨噬细胞机制研究阐明糖尿病引起的巨噬细胞途径
死亡,以及研究胰岛素受体信号减少导致增加的机制
T1 DM和Mets/T2 DM模型中APOC3水平的变化
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(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:
$ 40.47万 - 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:
$ 40.47万 - 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:
$ 40.47万 - 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:
$ 40.47万 - 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:
$ 40.47万 - 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:
$ 40.47万 - 项目类别:
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