Molecular Determinants of Arterial Remodeling in Atherogenesis

 描述(由申请人提供)：最近的研究发现了白介素1(IL-1)生物学和动脉重塑之间的意想不到的联系。缺乏IL-1信号受体(因此对IL-1α和β亚型均无反应)的APOE-/-小鼠在动脉粥样硬化形成过程中由于基质金属蛋白酶-3的表达减少而损害了扩张性重塑，并表现出斑块“不稳定”的证据，这可能是由于平滑肌细胞迁移受阻所致。其他非常新的数据质疑了IL-1β缺陷小鼠所获得的结果的有效性，并表明IL-1α亚型在动脉粥样硬化形成中的主要贡献。鉴于靶向IL-1亚型的能力 选择性地，正如我们正在进行的中和动脉粥样硬化患者IL-1β的大型研究(Canakinumab抗炎性血栓形成结果研究，CANTOS，NCT01900600)所表明的那样，严格定义IL-1亚型在动脉重构和动脉粥样硬化相关机制中的不同调节和贡献具有重要的生物学和临床意义。特殊目的1将在体外测试这一新的假说，即中度缺氧是一种普遍存在于斑块中的动脉粥样硬化相关刺激，通过不同的生化和细胞生物学机制调节巨噬细胞(MF)中IL-1α和IL-1β的产生。此外，这一目标将在人类细胞中测试IL-1亚型调节与先前资金时期的动脉重塑有关的蛋白酶的能力。我们将测试特定的假设，即IL-1的每个亚型都使这些细胞能够迁移，从而冗余地参与纤维帽的形成，并在动脉粥样硬化形成过程中参与扩张性重塑。特殊目的2将在体内测试这一假设，即在动脉粥样硬化易感小鼠中选择性抗体中和IL-1α或IL-1β将限制与动脉粥样硬化形成和已建立的动脉粥样斑块演变相关的机制，并且不会损害扩张性重塑或赋予斑块“不稳定”的特征，这两种异构体的阻断都是如此。这种方法将消除最近提出的关于使用Il1b-/-MICE的严重关切。《特殊目的3》将在人体上测试这一假设，即给予IL-1MMP3中和抗体将剂量依赖性地降低(但不是消除)血液中β-3的水平(以及在资源允许的情况下)与斑块不稳定和动脉重塑有关的其他蛋白酶。这一目标将进一步检验这一假设，即在一项由研究人员发起的大型临床试验CANTOS的安慰剂组内进行的嵌套病例对照研究中，发生动脉粥样硬化血栓并发症的个体比没有此类事件的匹配个体的血浆这些酶水平更高。CANTOS是为残余炎症负担而选择的人群。

 DESCRIPTION (provided by applicant): An unexpected connection between interleukin-1 (IL-1) biology and arterial remodeling has emerged from recent work. ApoE-/- mice deficient in the IL-1 signaling receptor (hence unresponsive to both IL-1 α and β isoforms) have impaired expansive remodeling during atherogenesis, attributable to reduced expression of matrix metalloproteinase (MMP)-3 by smooth muscle cells (SMCs), and exhibit evidence for plaque "instability", likely due to impaired SMC migration. Other very recent data have questioned the validity of results obtained with IL-1β deficient mice and have suggested a predominant contribution of the IL-1α isoform to atherogenesis. In view of the ability to target IL-1 isoforms selectively, as illustrated by our large ongoing study of neutralization of IL-1β in humans with atherosclerosis (Canakinumab Anti-Inflammatory Thrombosis Outcomes Study, CANTOS, NCT01900600), rigorously defining the distinct regulation and contributions of the IL-1 isoforms to mechanisms related to arterial remodeling and atherogenesis assumes critical biological and clinical significance. Specific Aim 1 will test in vitro the novel hypothesis that moderate hypoxia an atherosclerosis-related stimulus that prevails in plaques, regulates IL-1α and IL-1β production in macrophages (MFs), by distinct biochemical and cell-biological mechanisms. Further, this Aim will test in human cells the ability of IL-1 isoforms to regulate proteases implicated in arterial remodeling in the prior funding periods. We will test the specific hypothesi that IL-1 isoforms each enable these cells to migrate and hence participate redundantly in fibrous-cap formation, and in expansive remodeling during atherogenesis. Specific Aim 2 will test in vivo the hypothesis that selective antibody neutralization of IL-1α or IL-1β in atherosclerosis-susceptible mice will limit mechanisms related to atherogenesis and evolution of established atheromata, and will not impair expansive remodeling or confer characteristics of "instability" on plaques, as does blockade of both isoforms. This approach will obviate the serious concerns recently raised regarding the use of Il1b-/- mice. Specific Aim 3 will test in humans the hypothesis that administration of an IL-1β-neutralizing antibody will dose-dependently lower (but not extinguish) blood levels of MMP-3 (and as resources permit) other proteinases implicated in plaque instability and arterial remodeling. This Aim will further test th hypothesis that individuals who develop thrombotic complications of atherosclerosis have higher plasma levels of these enzymes than matched individuals without such events in a nested case-control study within the placebo group of a large ongoing investigator-initiated clinical trial, CANTOS, a population selected for residual inflammatory burden.