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Targeting NF-kB in Atherosclerosis

动脉粥样硬化中的靶向 NF-kB

基本信息

批准号：
8607585
负责人：
MICHAEL J MAY
金额：
$ 39.2万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-04-20 至 2015-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8607585
关键词：
Acute Address Affect Animals Apolipoprotein E Area Arterial Fatty Streak Arteries Atherosclerosis Automobile Driving Binding Biochemical Cell Adhesion Molecules Cell physiology Cell surface Cells Chronic Complex Development Disease Disease Progression Effectiveness Endothelial Cells Enzymes Event Family Future Gene Expression Gene Targeting Genetic Goals Health Healthcare Human In Vitro Inflammation Inflammatory Lesion Lymphocyte Modeling Molecular Mus NF-kappa B Names Outcome Output Pathway interactions Patients Peptides Play Principal Investigator Process Public Health Publishing Research Role Signal Transduction Smooth Muscle Myocytes Societies Staging Tertiary Protein Structure Testing Therapeutic Time Trefoil Motif United States atherogenesis base cell type chemokine cytokine design in vivo in vivo Model inhibitor/antagonist insight macrophage mortality mouse model novel novel therapeutics prevent public health relevance transcription factor

项目摘要

DESCRIPTION (provided by applicant): Atherosclerosis is a slowly progressing chronic inflammatory disease of the medium and large arteries that is responsible for high mortality rates in western society. Consequently, developing effective strategies to prevent or cure atherosclerosis is a highly significant objective that will profoundly impact human health care. At each stage of the disease, pro-atherogenic factors within the developing atherosclerotic lesion activate crucial cell types including endothelial cells (EC), smooth muscle cells and macrophages. When activated, these cells express cytokines, chemokines, cell surface molecules and enzymes that exacerbate atherogenesis. A major signaling mechanism associated with atherosclerosis is activation of the NF-kB family of transcription factors. Active NF-kB has been demonstrated in atherosclerotic plaques, and the importance of NF-kB for pro-atherogenic gene expression has been established in vitro. However, it remains unclear whether NF-:kB plays an overall positive or negative role during atherogenesis, and the effects of inhibiting NF-kB signaling on atherosclerosis in vivo are poorly understood. Furthermore, two major signaling mechanisms leading to the activation of distinct NF-kB species, named the classical and non-canonical NF-kB pathways, have been described recently. To date, only the classical pathway has been implicated in atherogenesis; however, emerging evidence strongly supports a role for the non-canonical pathway during the development of atherosclerosis. Our goal is to determine the overall effects of inhibiting NF-:kB signaling on the development of atherosclerosis. We will accomplish this using a combination of novel state-of-the-art pharmacological and genetic approaches that we have developed and by employing both in vitro and in vivo models of atherosclerosis. These approaches will provide both a deeper understanding of the molecular and biochemical mechanisms underlying disease progression and will determine the effectiveness of therapeutically blocking NF-kB in atherosclerosis. The hypothesis we will test is: "Inhibiting NF-kB activation will prevent the development of atherosclerosis". We will address this by pursuing the following three specific aims: (1) To define the roles of EC-intrinsic classical and NC NF-kB signaling during atherogenesis; (2) To determine the role of classical and NC NF-kB activation in pro-atherogenic signaling and gene expression in EC; (3) To determine the effects of the NEMO binding domain (NBD) peptide on atherosclerosis in vivo. These studies will directly address the role of the non-canonical NF-kB pathway in atherogenesis for the first time. Furthermore, the NBD peptide has never been tested in vivo in models of atherosclerosis and we predict that this unique approach will demonstrate that systemically blocking classical NF-kB signaling prevents the development of atherosclerosis. Successfully accomplishing our aims will provide crucial novel insight into the potential therapeutic value of targeting classical and non-canonical NF-kB signaling in atherosclerosis patients. Consequently, our proposal is highly significant and broadly impacts a critical area of human health concern.

描述（由申请人提供）：动脉粥样硬化是一种缓慢进展的中动脉和大动脉慢性炎症性疾病，是西方社会高死亡率的原因。因此，制定有效的策略来预防或治疗动脉粥样硬化是一个非常重要的目标，将深刻影响人类的医疗保健。在疾病的每个阶段，正在发展的动脉粥样硬化病变内的促动脉粥样硬化因子都会激活关键的细胞类型，包括内皮细胞（EC）、平滑肌细胞和巨噬细胞。当被激活时，这些细胞会表达细胞因子、趋化因子、细胞表面分子和酶，从而加剧动脉粥样硬化形成。与动脉粥样硬化相关的主要信号传导机制是转录因子 NF-kB 家族的激活。活性 NF-kB 已在动脉粥样硬化斑块中得到证实，并且 NF-kB 对于促动脉粥样硬化基因表达的重要性已在体外得到证实。然而，目前尚不清楚 NF-kB 在动脉粥样硬化形成过程中是否发挥总体积极或消极作用，并且抑制 NF-kB 信号传导对体内动脉粥样硬化的影响知之甚少。此外，最近描述了导致不同 NF-kB 种类激活的两种主要信号传导机制，称为经典和非经典 NF-kB 途径。迄今为止，只有经典途径与动脉粥样硬化形成有关。然而，新出现的证据强烈支持非典型途径在动脉粥样硬化发展过程中的作用。我们的目标是确定抑制 NF-:kB 信号传导对动脉粥样硬化发展的总体影响。我们将结合我们开发的新颖的最先进的药理学和遗传学方法以及采用动脉粥样硬化的体外和体内模型来实现这一目标。这些方法将加深对疾病进展的分子和生化机制的理解，并将确定阻断 NF-kB 在动脉粥样硬化治疗中的有效性。我们将测试的假设是：“抑制 NF-kB 激活将阻止动脉粥样硬化的发展”。我们将通过追求以下三个具体目标来解决这个问题：（1）定义 EC 内在经典信号和 NC NF-kB 信号在动脉粥样硬化形成过程中的作用； (2) 确定经典和 NC NF-kB 激活在 EC 中促动脉粥样硬化信号传导和基因表达中的作用； (3)确定NEMO结合域(NBD)肽对体内动脉粥样硬化的作用。这些研究将首次直接探讨非典型 NF-kB 通路在动脉粥样硬化形成中的作用。此外，NBD 肽从未在动脉粥样硬化模型中进行过体内测试，我们预测这种独特的方法将证明系统性阻断经典 NF-kB 信号传导可防止动脉粥样硬化的发展。成功实现我们的目标将为动脉粥样硬化患者靶向经典和非经典 NF-kB 信号传导的潜在治疗价值提供重要的新颖见解。因此，我们的建议非常重要，并且广泛影响人类健康问题的关键领域。

项目成果

期刊论文数量（8）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Noncanonical NF-κB activation and SDF-1 expression in human endothelial cells.

人内皮细胞中的非经典 NF-κB 激活和 SDF-1 表达。

DOI：
10.1007/978-1-4939-2422-6_9
发表时间：
2015
期刊：
Methods in molecular biology (Clifton, N.J.)
影响因子：
0
作者：
McCorkell,KellyA;May,MichaelJ
通讯作者：
May,MichaelJ

Sneaking-ligand fusion proteins attenuate serum transfer arthritis by endothelium-targeted NF-κB inhibition.

潜行配体融合蛋白通过内皮靶向 NF-κB 抑制来减轻血清转移关节炎。

DOI：
10.1007/978-1-4939-2422-6_34
发表时间：
2015
期刊：
Methods in molecular biology (Clifton, N.J.)
影响因子：
0
作者：
Sehnert,Bettina;Burkhardt,Harald;May,MichaelJ;Zwerina,Jochen;Voll,ReinhardE
通讯作者：
Voll,ReinhardE

NF-κB inhibitor targeted to activated endothelium demonstrates a critical role of endothelial NF-κB in immune-mediated diseases

DOI：
10.1073/pnas.1218219110
发表时间：
2013-10-08
期刊：
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
影响因子：
11.1
作者：
Sehnert, Bettina;Burkhardt, Harald;Voll, Reinhard Edmund
通讯作者：
Voll, Reinhard Edmund

Understanding high endothelial venules: Lessons for cancer immunology.