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流行疾病，每9人中就有1人受到影响。 他是吸烟者，每年在美国造成1万人有记录的死亡。AAA治疗仍然有效 仅限于大型动脉瘤的外科手术或血管内修复。这种缺乏有效的药物治疗反映了 关于AAA分子机制的现有知识空白，以及缺乏可靠的工具来 评价血管壁生物学并监测体内治疗效果。几个矩阵 金属蛋白酶(MMPs)，包括基质金属蛋白酶-12在人AAA中表达上调，许多MMPs已经 与AAA的发展有关。弹性蛋白降解是动脉瘤的关键特征，考虑使用基质金属蛋白酶-12 此设置中的主要弹性蛋白酶。关于基质金属蛋白酶-12在动脉瘤中的作用，有相互矛盾的数据 研究进展和新出现的信息表明，基质金属蛋白酶-12具有抗炎和促炎作用。 炎症性疾病。这结合我们的初步数据提出了一个耐人寻味的假设，即基质金属蛋白酶- 12在动脉瘤中具有双重作用：通过抑制中性粒细胞抑制早期动脉瘤的发展 血管壁上的再充填，并通过增强 血管壁发炎。在这里，我们介绍了用于高分辨率跟踪的新的分子成像技术 血管壁炎和基质金属蛋白酶/基质金属蛋白酶-12成像，与选择性抑制剂和 基因敲除小鼠将被用来a)研究基质金属蛋白酶/基质金属蛋白酶-12激活的时间和空间模式 与腹主动脉瘤的发生、发展和破裂的关系；以及b)阐述基质金属蛋白酶-12在动脉瘤中的作用。 血管重塑将用高分辨率多模式分子和结构成像进行跟踪 然后对两种互补的小鼠模型进行了组织形态计量学分析，即血管紧张素II诱导的 和氯化钙诱发的动脉瘤。脉管壁生物学、 对治疗的反应，以及动脉瘤的扩张和破裂，将通过在 同样的动物。基质金属蛋白酶-12基因缺失和基质金属蛋白酶-12抑制对动脉瘤形成的影响 已建立的动脉瘤的演变将被解决。结合起来，这些研究将解决新的方面 动脉瘤病理生物学，在临床前模型中验证新的治疗靶点，并建立新的成像 评价动脉瘤血管壁生物学的方法。归根结底，这应该会带来改善 管理AAA(和可能的其他血管疾病)患者；并减少相关发病率， 死亡率和医疗成本。

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