Mechanistic studies of disease progression in aortic aneurysms

主动脉瘤疾病进展的机制研究

• 批准号: 10427154
• 负责人: MEHRAN M SADEGHI
• 金额: --
• 依托单位: VA CONNECTICUT HEALTHCARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-01-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10427154
• 关键词: Abdominal Aortic Aneurysm; Address; Affect; Aneurysm; Angiotensin II; Animals; Aortic Aneurysm; Apolipoprotein E; Apolipoproteins; Biology; Calcium Chloride; Caliber; Cessation of life; Clinical Research; Clinical Trials; Conflict (Psychology); Data; Detection; Development; Disease; Disease Progression; Doxycycline; Effectiveness; Elastases; Elastin; Evaluation; Evolution; Future; Gene Deletion; Growth; Health; Health Care Costs; High Prevalence; Human; Image; Imaging Techniques; Immunity; Inflammation; Inflammatory; Knockout Mice; Knowledge; Lead; Link; Longitudinal Studies; MME gene; Matrix Metalloproteinase Inhibitor; Matrix Metalloproteinases; Measurement; Medical; Modeling; Molecular; Monitor; Morbidity - disease rate; Mus; Neutrophil Infiltration; Operative Surgical Procedures; Patients; Pattern; Play; Pre-Clinical Model; Resolution; Role; Rupture; Ruptured Abdominal Aortic Aneurysm; Smoker; Testing; Tissues; Vascular Diseases; Vascular remodeling; Veterans; X-Ray Computed Tomography; base; disease heterogeneity; disease mechanisms study; imaging approach; improved; in vivo; inhibitor; macrophage; molecular imaging; mortality; mouse model; multimodality; nanoparticle; new therapeutic target; non-drug; novel; nuclear imaging; patient population; preclinical study; prevent; repaired; risk stratification; serial imaging; spatial relationship; therapeutic effectiveness; therapeutic target; tool; treatment response

Abdominal aortic aneurysm (AAA), a prevalent disease amongst veterans, affects more than 1 in 9 smokers and is responsible for 10,000 documented deaths every year in the US. AAA treatment remains limited to surgical or endovascular repair for large aneurysms. This lack of an effective medical therapy reflects existing gaps in knowledge regarding the molecular mechanisms of AAA, and lack of reliable tools for evaluating vessel wall biology and monitoring therapeutic effectiveness in vivo. Several matrix metalloproteinases (MMPs), including MMP-12 are upregulated in human AAA, and a number of MMPs have been linked to AAA development. Elastin degradation is a key feature of aneurysm and MMP-12 is considered the primary elastase in this setting. There are conflicting data regarding the role of MMP-12 in aneurysm development and emerging information point to both anti- and pro-inflammatory functions for MMP-12 in inflammatory disorders. This in conjunction with our preliminary data raise the intriguing hypothesis that MMP- 12 plays a dual role in aneurysm: inhibiting early stage aneurysm development through inhibition of neutrophil recruitment to the vessel wall, and promoting expansion and rupture of established aneurysms by enhancing vessel wall inflammation. Here, we introduce novel molecular imaging techniques for high resolution tracking of vessel wall inflammation and MMP/MMP-12 imaging, which in conjunction with selective inhibitors and knockout mice will be used to a) investigate the temporal and spatial pattern of MMP/MMP-12 activation in relation to AAA development, progression and rupture; and b) address the role of MMP-12 in aneurysm. Vascular remodeling will be tracked with high resolution multimodality molecular and structural imaging followed by histomorphometric analysis in two complementary murine models, namely angiotensin II-induced and calcium chloride-induced aneurysms. The temporal and spatial relationship between vessel wall biology, response to therapy, and aneurysm expansion and rupture will be addressed through serial imaging in the same animal. The effects of MMP-12 gene deletion and MMP-12 inhibition on aneurysm development, and evolution of established aneurysms will be addressed. Combined, these studies will address novel aspects of aneurysm pathobiology, validate novel therapeutic targets in preclinical models, and establish novel imaging approaches for evaluation of vessel wall biology in aneurysms. Ultimately, this should lead to improved management of patients with AAA (and possibly other vascular diseases); and reduce related morbidity, mortality, and healthcare costs.

腹主动脉瘤 (AAA) 是退伍军人中的一种常见疾病，影响超过九分之一的退伍军人 吸烟者每年导致美国 10,000 人死亡。 AAA 治疗仍然有效 仅限于大动脉瘤的手术或血管内修复。缺乏有效的药物治疗反映出 关于 AAA 分子机制的知识存在差距，并且缺乏可靠的工具 评估血管壁生物学并监测体内治疗效果。几个矩阵 金属蛋白酶 (MMP)，包括 MMP-12，在人类 AAA 中表达上调，并且许多 MMP 与 AAA 开发相关。弹性蛋白降解是动脉瘤的一个关键特征，MMP-12 被认为是 在此设置中的主要弹性蛋白酶。关于 MMP-12 在动脉瘤中的作用存在相互矛盾的数据 开发和新出现的信息表明 MMP-12 具有抗炎和促炎功能 炎症性疾病。这与我们的初步数据相结合提出了一个有趣的假设，即 MMP- 12 在动脉瘤中发挥双重作用：通过抑制中性粒细胞来抑制早期动脉瘤的发展 募集到血管壁，并通过增强来促进已建立的动脉瘤的扩张和破裂 血管壁炎症。在这里，我们介绍了用于高分辨率跟踪的新颖分子成像技术 血管壁炎症和 MMP/MMP-12 成像，与选择性抑制剂和 敲除小鼠将用于 a) 研究 MMP/MMP-12 激活的时间和空间模式 与 AAA 发展、进展和破裂的关系； b) 探讨 MMP-12 在动脉瘤中的作用。 将通过高分辨率多模态分子和结构成像来跟踪血管重塑 随后在两个互补的小鼠模型（即血管紧张素 II 诱导的模型）中进行组织形态计量学分析 和氯化钙引起的动脉瘤。血管壁生物学之间的时间和空间关系， 对治疗的反应以及动脉瘤扩张和破裂将通过连续成像来解决 同一种动物。 MMP-12 基因缺失和 MMP-12 抑制对动脉瘤发展的影响，以及 将解决已形成的动脉瘤的演变。结合起来，这些研究将解决以下新的方面： 动脉瘤病理学，在临床前模型中验证新的治疗靶点，并建立新的成像 评估动脉瘤血管壁生物学的方法。最终，这应该会导致改进 AAA（以及可能的其他血管疾病）患者的管理；并减少相关发病率， 死亡率和医疗费用。

项目成果

Novel Matrix Metalloproteinase 12 selective radiotracers for vascular molecular imaging.

• DOI: 10.1021/acs.jmedchem.9b01186
• 发表时间: 2019-10
• 期刊: Journal of medicinal chemistry
• 影响因子: 7.3
• 作者: Jakub Toczek;Thomas Bordenave;K. Gona;Hye-Yeong Kim;F. Beau;D. Georgiadis;Isabelle Correia;Y. Ye;Mahmoud Razavian;Jaejoon Jung;O. Lequin;V. Dive;M. Sadeghi;L. Devel

Deletion of matrix metalloproteinase-12 compromises mechanical homeostasis and leads to an aged aortic phenotype in young mice.

• DOI: 10.1016/j.jbiomech.2022.111179
• 发表时间: 2022-08
• 期刊: JOURNAL OF BIOMECHANICS
• 影响因子: 2.4
• 作者: Spronck, Bart;Ramachandra, Abhay B.;Moriyama, Lauren;Toczek, Jakub;Han, Jinah;Sadeghi, Mehran M.;Humphrey, Jay D.
• 通讯作者: Humphrey, Jay D.

Computed tomography imaging of macrophage phagocytic activity in abdominal aortic aneurysm.

• DOI: 10.7150/thno.55106
• 发表时间: 2021
• 期刊: Theranostics
• 影响因子: 12.4
• 作者: Toczek J;Boodagh P;Sanzida N;Ghim M;Salarian M;Gona K;Kukreja G;Rajendran S;Wei L;Han J;Zhang J;Jung JJ;Graham M;Liu X;Sadeghi MM
• 通讯作者: Sadeghi MM

ESDN inhibits melanoma progression by blocking E-selectin expression in endothelial cells via STAT3.

• DOI: 10.1016/j.canlet.2021.04.005
• 发表时间: 2021-07-10
• 期刊: Cancer letters
• 影响因子: 9.7
• 作者: Coppo R;Orso F;Virga F;Dalmasso A;Baruffaldi D;Nie L;Clapero F;Dettori D;Quirico L;Grassi E;Defilippi P;Provero P;Valdembri D;Serini G;Sadeghi MM;Mazzone M;Taverna D
• 通讯作者: Taverna D