Targeting Cadherin-11 for the Treatment of Calcific Aortic Valve Disease

靶向钙粘蛋白 11 治疗钙化性主动脉瓣疾病

• 批准号: 10328482
• 负责人: Lance Riley
• 金额: $ 4.63万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2022-03-25
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10328482
• 关键词: Adhesions; Affect; Affinity; Age-Months; Aging; Antibodies; Aortic Valve Stenosis; Atomic Force Microscopy; Binding; Binding Sites; Blocking Antibodies; Cadherins; Cardiac; Cell Adhesion Molecules; Cell-Cell Adhesion; Cells; Cessation of life; Clinic; Clinical; Collagen; Coxibs; Cytoskeleton; DNA; Data; Development; Dimethyl Sulfoxide; Disease; Disease Progression; Disease model; Dystrophic Calcification; Effectiveness; Elderly; Extracellular Domain; Extracellular Protein; Fellowship; Fibroblasts; Fluorescence-Activated Cell Sorting; Gene Expression; Goals; Heart Diseases; Heart Valve Prosthesis; Heart Valves; Hematopoietic; Human; IL-6 inhibitor; In Vitro; Inflammatory; Inflammatory Response; Injections; Integral Membrane Protein; Interleukin-6; Intervention; Matrix Metalloproteinases; Mediating; Modeling; Monitor; Monoclonal Antibodies; Morbidity - disease rate; Mus; Nodule; North America; Onset of illness; Operative Surgical Procedures; Oral; Patients; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacology; Phenotype; Population; Preclinical Testing; Prevention; Preventive therapy; Proteins; Pump; Research; Signal Transduction; Stenosis; Structure; Sulfonamides; Testing; Therapeutic; Tissues; Translating; Translations; Ultrasonography; United States; analog; aortic valve; aortic valve disorder; aortic valve replacement; cadherin-11; calcification; celecoxib; cell type; cytokine; experimental study; heart function; hemodynamics; high throughput screening; human old age (65+); in vivo; insight; interstitial; interstitial cell; macrophage; monocyte; mortality; mouse model; neutrophil; novel; novel therapeutics; peripheral blood; pre-clinical; prevent; recruit; screening; small molecule; small molecule libraries; treatment choice; valve replacement

Project Summary Calcific aortic valve disease (CAVD) is the most common affliction of the cardiac valves and is becoming more prevalent in aging populations. It is a notoriously difficult disease to study and treat, and is responsible for approximately 15,000 deaths per year in North America. Currently, the only effective, long-term treatments for CAVD are surgical or transcatheter aortic valve replacements; however, these replacements are only recommended for patients with severe aortic stenosis or in patients undergoing surgery for another form of heart disease. There is no preventative therapy or pharmacological intervention to treat CAVD as the mechanisms underlying this disease’s progression are poorly understood. Our lab has implicated the cell-cell adhesion protein cadherin-11 (CDH11) in this disease and shown that blocking this protein with a monoclonal antibody prevents every aspect of CAVD. While this antibody provides hope, it is not clinically translatable, as it would require asymptomatic patients to receive monthly injections to prevent a disease that can take years to present. Thus, development of novel pharmaceuticals is needed to prevent this disease. Previous research indicates that the COX2 inhibitor celecoxib binds to CDH11, but is associated with aortic stenosis in human patients. Preliminary results from our lab indicate the inactive analog celecoxib, dimethyl celecoxib, could be a small molecule that prevents CAVD both in vitro and in vivo as it also binds CDH11 but prevents several hallmarks of CAVD in vitro. Additionally, analysis of the structural similarities between celecoxib and dimethyl celecoxib indicate that sulfonamides could be a useful class of small molecules for targeting CDH11. The goal of this study is to identify CDH11-binding small molecules that block the progression of CAVD and determine the disease mechanisms that are altered in vitro when these drugs are administered. We present two primary aims: 1) determine the efficacy of dimethyl celecoxib as a therapeutic for CAVD in vivo and 2) identify novel CDH11 binding compounds through the use of high-throughput, small molecule screening. This study will be the first to demonstrate the effectiveness of small molecules in preventing CAVD and will provide insight into the mechanisms that cause this disease.

项目摘要 钙化性主动脉瓣疾病（CAVD）是心脏瓣膜最常见的疾病， 在老龄化人群中普遍存在。这是一种众所周知的难以研究和治疗的疾病， 在北美每年大约有15,000人死亡。目前，唯一有效的长期治疗方法 CAVD是外科手术或经导管主动脉瓣置换术;然而，这些置换术仅 推荐用于严重主动脉瓣狭窄患者或因其他形式的 心脏病没有预防性治疗或药物干预来治疗CAVD， 这种疾病进展的潜在机制知之甚少。我们的实验室发现细胞-细胞 粘附蛋白钙粘蛋白-11（CDH 11）在这种疾病中的作用，并表明用单克隆抗体阻断该蛋白 抗体可以预防CAVD的各个方面。虽然这种抗体带来了希望，但它在临床上是不可翻译的，因为它 将要求无症状的患者每月接受注射，以预防可能需要数年时间才能治愈的疾病。 礼物因此，需要开发新的药物来预防这种疾病。以前的研究 表明COX 2抑制剂塞来昔布与CDH 11结合，但与人体主动脉瓣狭窄相关 患者我们实验室的初步结果表明，非活性类似物塞来昔布，二甲基塞来昔布，可能是一种 在体外和体内都能预防CAVD的小分子，因为它也能结合CDH 11，但也能预防几种CAVD。 体外CAVD的标志。此外，分析塞来昔布和二甲基甲酰胺之间的结构相似性， 塞来昔布表明磺胺类药物可能是靶向CDH 11的一类有用的小分子。目标 本研究的目的是鉴定阻断CAVD进展的CDH 11结合小分子， 当这些药物被施用时，疾病机制在体外改变。我们提出了两个主要的 目的：1）确定二甲基塞来昔布作为体内CAVD治疗剂的疗效，2）鉴定新的 通过使用高通量、小分子筛选来结合CDH 11的化合物。本研究将 第一个证明小分子在预防CAVD中的有效性，并将提供深入了解 导致这种疾病的机制。

项目成果

Cadherin-11 and cardiac fibrosis: A common target for a common pathology.

• DOI: 10.1016/j.cellsig.2020.109876
• 发表时间: 2021-03
• 期刊: Cellular signalling
• 影响因子: 4.8
• 作者: Riley LA;Merryman WD
• 通讯作者: Merryman WD

Sclerostin ablation prevents aortic valve stenosis in mice.

硬化蛋白消融可预防小鼠主动脉瓣狭窄。

• DOI: 10.1152/ajpheart.00355.2022
• 发表时间: 2022
• 期刊: American journal of physiology. Heart and circulatory physiology
• 作者: Joll2nd,JEthan;Riley,LanceA;Bersi,MatthewR;Nyman,JeffryS;Merryman,WDavid
• 通讯作者: Merryman,WDavid

Loss of talin in cardiac fibroblasts results in augmented ventricular cardiomyocyte hypertrophy in response to pressure overload.

心脏成纤维细胞中talin的缺失导致压力超负荷时心室心肌细胞肥大加剧。

• DOI: 10.1152/ajpheart.00632.2021
• 发表时间: 2022
• 期刊: American journal of physiology. Heart and circulatory physiology
• 作者: Noll,NatalieA;Riley,LanceA;Moore,ChristyS;Zhong,Lin;Bersi,MathewR;West,JamesD;Zent,Roy;Merryman,WDavid
• 通讯作者: Merryman,WDavid