Insulin-Like Growth Factor-1 and Atherosclerosis

胰岛素样生长因子 1 与动脉粥样硬化

基本信息

批准号：
10744484
负责人：
PATRICE DELAFONTAINE
金额：
$ 69.2万
依托单位：
TULANE UNIVERSITY OF LOUISIANA
依托单位国家：
美国
项目类别：
财政年份：
2002
资助国家：
美国
起止时间：
2002-12-05 至 2027-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10744484
关键词：
Aging Animal Model Antibodies Aorta Aortic Diseases Apolipoprotein E Arterial Fatty Streak Atherosclerosis Biology Cardiovascular Diseases Cause of Death Cell Aging Cell Senescence Induction Cells Chromosome Mapping Chronic Disease Clinical Trials Conditioned Culture Media Coronary Coronary artery Coronary heart disease Data Deposition Development Diabetes Mellitus Disease Endothelial Cells Event Excision Familial Hypercholesterolemia Family suidae Gene Expression Genes Genetic Goals Growth Histology Human Hypertension In Vitro Insulin Insulin-Like Growth Factor I Insulin-Like Growth-Factor-Binding Proteins Insulin-Like-Growth Factor I Receptor Invertebrates Ischemia Laboratories Lipids Lipopolysaccharides Longevity Macrophage Manuscripts Modeling Morbidity - disease rate Mus Myocardial Infarction Patients Pharmaceutical Preparations Phenotype Play Population Prevention Printing Receptor Signaling Resistance Risk Risk Factors Rodent Role Signal Transduction Smoking Smooth Muscle Myocytes Technology Testing Thinness Tissue Sample Vascular Smooth Muscle Vascularization atherogenesis cardiovascular disorder therapy cell type cellular longevity cerebral artery coronary plaque deprivation gain of function human disease improved in vitro Model inhibitor innovation insight insulin-like growth factor binding protein-related protein 1 laser capture microdissection loss of function member mortality mouse model novel novel drug class novel therapeutics optimal treatments prevent senescence single-cell RNA sequencing subcutaneous transcriptomics virtual

项目摘要

PROJECT SUMMARY / ABSTRACT Coronary heart disease is a primary contributor to cardiovascular disease worldwide. Despite optimal treatment many patients remain vulnerable to ischemic events. While small animal models have proven extraordinarily effective at exploring mechanisms, studies in large animal models are critically needed, as a bridge between rodent studies and human trials, and to develop new therapies. We have shown that insulin-like growth factor-1 (IGF-1) reduces atherosclerotic burden and promotes features of plaque stability in Apoe-/- mice and in Rapacz swine with familial hypercholesterolemia (FH pigs). Our novel findings indicate that IGF-1 reduces the number of senescent cells, including senescent SMC-like and MF-like cells in pig coronary atherosclerotic plaques, in particular in the fibrous cap (FC). Cellular senescence is thought to play a vital role in aging and in the development of chronic disease. However, the relation between IGF-1, cell senescence and atherosclerotic disease is virtually unknown. Senescent cells contribute to atherogenesis and fibrous cap thinning in mouse models, but there is no information on the causal role of cell senescence in atherogenesis in large animal models or in humans. Using scRNA-seq analysis of aortas from Apoe-/- mice and spatial transcriptomics analysis of porcine plaque we show high-level expression of the senescence-associated secretory phenotype (SASP) factor IGF binding Protein-7 (IGFBP7), an IGF-1 inhibitor, in the fibrous cap, primarily localized to SMC-like cells, particularly fibromyocytes. Elevated senescence scores are strongly associated with fibromyocytes and high IGFBP7 expression. We hypothesize that senescent cells inhibit IGF-1 signaling and that SASP-induced IGF-1 resistance reduces anti-atherosclerotic effects of IGF-1. Our data shows that conditioned medium from senescent cultured SMC inhibits IGF1R signaling in SMC, an effect reversed by anti-IGFBP7 antibody. Our overall goal is to demonstrate that removal of senescent cells using a senolytic, ABT263, will reduce atherosclerosis in a large animal model and potentiate anti-atherosclerotic effects of IGF-I. We will also demonstrate the role of IGFBP7 in IGF-1 resistance using a loss-of-function murine model, and further explore mechanisms using in vitro studies. Specific Aim 1: Test the hypothesis that clearance of senescent cells using a senolytic in a large animal model of atherosclerosis will reduce atherosclerotic burden and potentiate IGF-1 ability to reduce atherosclerotic burden and promote plaque stability. scRNA-seq, spatial transcriptomics, multi-marker histology, and laser capture microdissection (LCM) will be used to dissect mechanisms. Specific Aim 2: Specific Aim 2: Demonstrate that genetic deprivation of IGFBP7 in SMC-like cells enhances anti-atherosclerosis effects of IGF-1. We will use SMC-selective IGFBP7-deficient mice, scRNA- seq analysis and in vitro models to dissect mechanisms.

项目概要/摘要冠心病是全世界心血管疾病的主要原因。尽管进行了最佳治疗许多患者仍然容易受到缺血事件的影响。虽然小动物模型已被证明具有非凡的为了有效地探索机制，迫切需要对大型动物模型进行研究，作为两者之间的桥梁啮齿动物研究和人体试验，并开发新疗法。我们已经证明胰岛素样生长因子-1 (IGF-1) 可减少 Apoe-/- 小鼠和 Rapacz 小鼠的动脉粥样硬化负担并促进斑块稳定性特征患有家族性高胆固醇血症的猪（FH 猪）。我们的新发现表明 IGF-1 可以减少猪冠状动脉中衰老细胞的数量，包括衰老的 SMC 样细胞和 MF 样细胞动脉粥样硬化斑块，特别是纤维帽 (FC) 中的斑块。细胞衰老被认为起着至关重要的作用在衰老和慢性疾病发展中的作用。然而，IGF-1与细胞衰老之间的关系动脉粥样硬化疾病几乎是未知的。衰老细胞导致动脉粥样硬化和纤维帽小鼠模型中细胞变薄，但没有关于细胞衰老在动脉粥样硬化形成中的因果作用的信息大型动物模型或人类。使用 scRNA-seq 分析 Apoe-/- 小鼠的主动脉和空间通过对猪斑块的转录组学分析，我们发现衰老相关蛋白的高水平表达分泌表型 (SASP) 因子 IGF 结合蛋白 7 (IGFBP7)，一种 IGF-1 抑制剂，位于纤维帽中，主要定位于 SMC 样细胞，特别是纤维肌细胞。衰老分数的升高强烈与纤维肌细胞和 IGFBP7 高表达相关。我们假设衰老细胞抑制 IGF-1 信号传导和 SASP 诱导的 IGF-1 抵抗降低了 IGF-1 的抗动脉粥样硬化作用。我们的数据表明，来自衰老培养 SMC 的条件培养基可抑制 SMC 中的 IGF1R 信号传导，这是一种抗 IGFBP7 抗体可逆转该效应。我们的总体目标是证明去除衰老细胞使用 senolytic ABT263 将减少大型动物模型中的动脉粥样硬化并增强抗动脉粥样硬化 IGF-I 的作用。我们还将使用功能丧失的小鼠来证明 IGFBP7 在 IGF-1 抗性中的作用模型，并利用体外研究进一步探索机制。具体目标 1：测试以下假设：在大型动物中使用 senolytic 清除衰老细胞动脉粥样硬化模型将减轻动脉粥样硬化负担并增强 IGF-1 减少动脉粥样硬化的能力动脉粥样硬化负担并促进斑块稳定性。 scRNA-seq、空间转录组学、多标记组织学和激光捕获显微切割（LCM）将用于解剖机制。具体目标 2：具体目标 2：证明 SMC 样细胞中 IGFBP7 的遗传剥夺增强IGF-1的抗动脉粥样硬化作用。我们将使用 SMC 选择性 IGFBP7 缺陷小鼠，scRNA- seq 分析和体外模型来剖析机制。

项目成果

期刊论文数量（74）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Interleukin-18/WNT1-inducible signaling pathway protein-1 signaling mediates human saphenous vein smooth muscle cell proliferation.

Interleukin-18/WNT1 诱导信号通路 Protein-1 信号介导人隐静脉平滑肌细胞增殖。

DOI：
发表时间：
2011-12
期刊：
影响因子：
5.6
作者：
Reddy, Venkatapuram Seenu;Valente, Anthony J;Delafontaine, Patrice;Chandrasekar, Bysani
通讯作者：
Chandrasekar, Bysani

Angiotensin II, oxidative stress and skeletal muscle wasting.

血管紧张素 II、氧化应激和骨骼肌萎缩。

DOI：
发表时间：
2011-08
期刊：
影响因子：
0
作者：
Sukhanov, Sergiy;Semprun;Yoshida, Tadashi;Michael Tabony, A;Higashi, Yusuke;Galvez, Sarah;Delafontaine, Patrice
通讯作者：
Delafontaine, Patrice

Angiotensin II upregulates protein phosphatase 2Cα and inhibits AMP-activated protein kinase signaling and energy balance leading to skeletal muscle wasting.

血管紧张素 II 上调蛋白磷酸酶 2Cα 并抑制 AMP 激活的蛋白激酶信号传导和能量平衡，导致骨骼肌消耗。

DOI：
发表时间：
2011-10
期刊：
影响因子：
0
作者：
Tabony, A Michael;Yoshida, Tadashi;Galvez, Sarah;Higashi, Yusuke;Sukhanov, Sergiy;Chandrasekar, Bysani;Mitch, William E;Delafontaine, Patrice
通讯作者：
Delafontaine, Patrice

Nuclear complex of glyceraldehyde-3-phosphate dehydrogenase and DNA repair enzyme apurinic/apyrimidinic endonuclease I protect smooth muscle cells against oxidant-induced cell death.

3-磷酸甘油醛脱氢酶和 DNA 修复酶脱嘌呤/脱嘧啶核酸内切酶 I 的核复合物可保护平滑肌细胞免受氧化剂诱导的细胞死亡。

DOI：
发表时间：
2017-07
期刊：
影响因子：
0
作者：
Hou, Xuwei;Snarski, Patricia;Higashi, Yusuke;Yoshida, Tadashi;Jurkevich, Alexander;Delafontaine, Patrick;Sukhanov, Sergiy
通讯作者：
Sukhanov, Sergiy

An Intronic Enhancer Element Regulates Angiotensin II Type 2 Receptor Expression during Satellite Cell Differentiation, and Its Activity Is Suppressed in Congestive Heart Failure.

内含子增强子元件在卫星细胞分化过程中调节血管紧张素 II 2 型受体表达，并且其活性在充血性心力衰竭中受到抑制。