Novel Regulators of Calcific Aortic Valve Disease

钙化性主动脉瓣疾病的新型调节剂

• 批准号: 9922787
• 负责人: MEHRAN M SADEGHI
• 金额: $ 70.73万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-06-01 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9922787
• 关键词: Address; Age; Animal Model; Animals; Aortic Valve Stenosis; Atherosclerosis; Biochemical; Biological Assay; Blood Vessels; Calcinosis; Cardiovascular system; Cell Culture Techniques; Cell physiology; Cells; Cessation of life; Data; Detection; Development; Disease; Disease Progression; Down-Regulation; Echocardiography; Endothelium; Experimental Models; Extracellular Matrix; Familial disease; Family; Family member; Fibrosis; Functional Imaging; Functional disorder; Gender; Genetic; Genetic Predisposition to Disease; Growth Factor; Heart Valve Diseases; Histologic; Human; Hyperlipidemia; Hypertension; Image; Imaging Device; Imaging Techniques; Incidence; Inflammation; Lead; Longitudinal Studies; Matrix Metalloproteinases; Medical; Metabolic syndrome; Modeling; Molecular; Molecular Target; Morbidity - disease rate; Mus; Mutation; Neuropilins; Osteogenesis; Pathogenesis; Pathology; Pathway interactions; Patients; Pattern; Performance; Play; Pre-Clinical Model; Proteins; Regulation; Reporting; Risk Factors; Risk stratification; Role; Signal Pathway; Signal Transduction; Single-Gene Defect; Smooth Muscle; Stenosis; Structure; Techniques; Therapeutic Intervention; Tobacco use; Validation; Vascular remodeling; X-Ray Computed Tomography; aged; aortic valve; aortic valve disorder; bicuspid aortic valve; calcification; cell transformation; clinical translation; hemodynamics; human disease; hypercholesterolemia; imaging detection; imaging modality; improved; in vivo; interstitial cell; intervention effect; member; modifiable risk; molecular imaging; mortality; mouse model; new therapeutic target; notch protein; novel; novel therapeutics; outcome prediction; targeted treatment; tool; valve replacement

Aortic stenosis is the most common cause of valvular heart disease and calcific aortic valve disease (CAVD) is the most common cause of aortic stenosis. There is currently no medical therapy, except for invasive valve replacement in symptomatic patients, for CAVD. This is mainly due to poor understanding of pathophysiology, in part due to lack of appropriate animal models, and lack of appropriate tools for risk stratification and tracking the effect of interventions in vivo. Beside traditional risk factors, age, gender, tobacco use, hypercholesterolemia, and hypertension, genetic background is an important determinant of CAVD. The effect of genetic background is best recognized in bicuspid aortic valve (BAV), the major cause of advanced CAVD and aortic stenosis in younger subjects. There is ongoing debate on whether hemodynamic alterations, genetic and cellular factors, or both lead to early development of CAVD in BAV. Valvular interstitial cell transformation, extracellular matrix remodeling (including fibrosis) and calcification are pathologic hallmarks of CAVD and play a central role in its pathogenesis. Several signaling pathways (e.g., Notch) which regulate bone formation are implicated in the pathogenesis of CAVD, and could potentially serve as targets for therapeutic interventions aimed at slowing down the progression of the disease. Endothelial and smooth muscle neuropilin-like protein (ESDN) is a marker of vascular remodeling and regulator of growth factor signaling in vascular cells. Interestingly, there is a high incidence of BAV (~50%) in Esdn-/- animals, and in preliminary studies we have observed spontaneous development of CAVD in aged Esdn-/- mice. These findings will be leveraged to address the aforementioned gaps in CAVD pathobiology and imaging, by investigating the role of the neuropilin-like protein, ESDN in experimental calcific aortic valve disease, and to examine the interplay between leaflet numbers, modifiable risk factors and genetic background in CAVD, while establishing novel molecular imaging techniques for tracking the effect of interventions and prediction of outcome in CAVD. These studies will lead to better understating of CAVD pathophysiology and potentially novel therapeutic targets to mitigate CAVD progression. In parallel, they will establish novel molecular imaging tools for risk stratification in CAVD with high potential for clinical translation.

主动脉瓣狭窄是心脏瓣膜病和主动脉钙化最常见的原因 瓣膜病（CAVD）是主动脉瓣狭窄的最常见原因。目前没有 CAVD的药物治疗，有症状患者的侵入性瓣膜置换术除外。这 主要是由于对病理生理学的认识不足，部分原因是缺乏适当的 动物模型，缺乏适当的工具进行风险分层和跟踪的影响， 体内干预。除了传统的风险因素，年龄，性别，烟草使用， 高胆固醇血症和高血压，遗传背景是一个重要的决定因素 CAVD。遗传背景的影响在二叶式主动脉瓣（BAV）中得到最好的认识， 是年轻受试者中晚期CAVD和主动脉瓣狭窄的主要原因。目前正在 关于血流动力学改变、遗传和细胞因素或两者是否导致早期 BAV中CAVD的发展。瓣膜间质细胞转化，细胞外基质 重塑（包括纤维化）和钙化是CAVD的病理标志， 在其发病机制中发挥核心作用。几种信号通路（例如，Notch）调节骨 CAVD的发病机制中有牵连，并可能作为靶点， 旨在减缓疾病进展的治疗干预。内皮和 平滑肌神经纤毛蛋白样蛋白（ESDN）是血管重塑标志物和调节剂 血管细胞中的生长因子信号。有趣的是， （~50%），在初步研究中，我们观察到自发性 老年Esdn-/-小鼠中CAVD的发展。这些调查结果将被用来解决 上述CAVD病理生物学和成像的差距，通过研究的作用， 神经纤毛蛋白样蛋白，ESDN在实验性钙化性主动脉瓣疾病，并检查 CAVD中瓣叶数量、可改变的危险因素和遗传背景之间的相互作用， 同时建立了新的分子成像技术来跟踪干预的效果， 预测CAVD的预后。这些研究将有助于更好地了解CAVD 病理生理学和潜在的新型治疗靶点，以缓解CAVD进展。在 同时，他们将建立新的分子成像工具，用于CAVD高风险分层。 临床翻译的潜力。

项目成果

Novel Arginine-containing Macrocyclic MMP Inhibitors: Synthesis, 99mTc-labeling, and Evaluation.

新型含精氨酸大环 MMP 抑制剂：合成、99mTc 标记和评估。

• DOI: 10.1038/s41598-018-29941-2
• 发表时间: 2018
• 期刊: Scientific reports
• 影响因子: 4.6
• 作者: Ye,Yunpeng;Toczek,Jakub;Gona,Kiran;Kim,Hye-Yeong;Han,Jinah;Razavian,Mahmoud;Golestani,Reza;Zhang,Jiasheng;Wu,TerenceL;Ghosh,Mousumi;Jung,Jae-Joon;Sadeghi,MehranM
• 通讯作者: Sadeghi,MehranM