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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

基本信息

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
项目类别：
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

项目摘要

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.

项目总结

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

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
影响因子：
0
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
影响因子：
0
作者：
Noll,NatalieA;Riley,LanceA;Moore,ChristyS;Zhong,Lin;Bersi,MathewR;West,JamesD;Zent,Roy;Merryman,WDavid
通讯作者：
Merryman,WDavid