Targeting NF-kB in Atherosclerosis

动脉粥样硬化中的靶向 NF-kB

• 批准号: 8258725
• 负责人: MICHAEL J MAY
• 金额: $ 40万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-20 至 2015-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8258725
• 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

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. PUBLIC HEALTH RELEVANCE: Atherosclerosis is a chronic inflammatory disease of the large arteries that has a high mortality rate in the United States and other western societies. We will use novel state-of-the-art genetic and pharmacological approaches to define the cellular signals that play a critical role in the development of atherosclerosis. Our studies will directly impact public health, as they will provide crucial insight for future therapeutics designed to inhibit the major pro-inflammatory signals driving atherosclerosis.

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，在西方社会造成高死亡率。因此，开发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，将深刻影响人类的健康护理。在疾病的每个阶段，发展中的动脉粥样硬化病变内的促动脉粥样硬化因子激活关键细胞类型，包括内皮细胞（EC）、平滑肌细胞和巨噬细胞。当被激活时，这些细胞表达加剧动脉粥样硬化形成的细胞因子、趋化因子、细胞表面分子和酶。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。在动脉粥样硬化斑块中已经证实了活性NF-kB，并且已经在体外确定了NF-kB对于促动脉粥样硬化基因表达的重要性。然而，目前还不清楚NF-κ B在动脉粥样硬化形成过程中是否起着积极或消极的作用，抑制NF-κ B信号转导对体内动脉粥样硬化的影响也知之甚少。此外，最近已经描述了导致不同NF-κ B种类激活的两种主要信号传导机制，称为经典和非经典NF-κ B途径。到目前为止，只有经典途径与动脉粥样硬化发生有关;然而，新出现的证据强烈支持非经典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。我们将结合使用我们开发的新型最先进的药理学和遗传学方法，并采用动脉粥样硬化的体外和体内模型来实现这一目标。这些方法将提供对疾病进展的分子和生化机制的更深入理解，并将确定治疗性阻断NF-κ B在动脉粥样硬化中的有效性。我们将检验的假设是：“抑制NF-κ B活化将防止动脉粥样硬化的发展”。我们将通过以下三个具体目标来解决这个问题：（1）确定EC内在经典和NC NF-κ B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-κ B激活在EC促动脉粥样硬化信号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影响。这些研究将首次直接阐明非经典NF-κ B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-κ B信号传导可预防动脉粥样硬化的发展。成功地实现我们的目标将提供关键的新的洞察力的潜在治疗价值的靶向经典和非经典的NF-κ B信号在动脉粥样硬化患者。因此，我们的建议非常重要，广泛影响人类健康关切的一个关键领域。 公共卫生相关性：动脉粥样硬化是一种大动脉的慢性炎症性疾病，在美国和其他西方社会具有高死亡率。我们将使用最先进的遗传学和药理学方法来确定在动脉粥样硬化发展中起关键作用的细胞信号。我们的研究将直接影响公共卫生，因为它们将为未来旨在抑制驱动动脉粥样硬化的主要促炎信号的治疗提供关键的见解。