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Medical Therapies in the Treatment of Calcific Aortic Valve Disease

钙化性主动脉瓣疾病的药物治疗

基本信息

批准号：
10449395
负责人：
Joy Lincoln
金额：
$ 42.49万
依托单位：
MEDICAL COLLEGE OF WISCONSIN
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-01 至 2024-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10449395
关键词：
Address Attenuated Basic Science Biomechanics Blood flow Cells Cessation of life Characteristics Chondrocytes Clinical Collagen Cre-LoxP Data Development Disease Elastin Fiber Extracellular Matrix Family suidae Fibroblasts Goals Heart Valve Diseases Homeostasis Human In Vitro Individual Intestines Lead Left Malignant Neoplasms Mediating Medical Mus Nodule Nuclear Nuclear Export Operative Surgical Procedures Oral Osteoblasts Pathway interactions Patient-Focused Outcomes Pharmaceutical Preparations Pharmacological Treatment Pharmacology Phase Phase III Clinical Trials Phenotype Process Property Proteoglycan Proteomics Public Health Research Signal Pathway Signal Transduction Stenosis Structure Surface Testing Therapeutic United States WNT Signaling Pathway Work aging population aortic valve aortic valve disorder base calcification cell type improved in vivo inhibitor inhibitor therapy interstitial cell loss of function mouse model novel novel therapeutics osteogenic prevent success therapeutic evaluation therapeutic target trafficking transcription factor

项目摘要

PROJECT SUMMARY Heart valve disease results in over 23,000 annual deaths in the United States with calcific aortic valve disease (CAVD) being the most prevalent. There is no pharmacological treatment to prevent or reverse CAVD and therefore surgical intervention remains the only effective option which comes with insuperable complications and no guarantee of long-term success. In healthy individuals, valve leaflets maintain unidirectional blood flow by sustaining a highly organized extracellular matrix (ECM) structure. The major resident cell type responsible for ECM homeostasis is the valve interstitial cell (VIC) that resembles a fibroblast in healthy individuals. In CAVD, VICs transition towards an osteoblast-like cells and this is associated with perturbations in ECM organization including calcific nodule formation on the aortic surface leading to stenosis. Despite this, the signaling pathways underlying osteogenic changes in valve structures are not known and therefore the development of pharmacological therapies to attenuate or reverse the process have been stalled. KPT-330 is a CRM1-dependent nuclear export inhibitor currently in Phase III clinical trials to treat cancer. We show that KPT-330 is sufficient to prevent CAVD in mice (Klotho-/-), as well as prevent, attenuate and rescue calcific nodule formation in human and porcine aortic VICs in vitro. The mechanism underlying the beneficial effect of KPT-330 in CAVD is not known, but our proteomic analysis suggests that it inhibits nuclear export of the CRM1-dependent transcription factor, NFAT5 to reduce calcification. The goal of this proposal is to further test the therapeutic potential of KPT-330 in the treatment of CAVD and delineate the mechanisms underlying its function. Work by us and others has shown that human CAVD is associated with reduced Sox9 and increased Wnt signaling. Interestingly, studies in chondrocytes and intestinal cells have shown that Sox9 and Wnt are commonly regulated by NFAT5, albeit in opposing directions. We have preliminary data to suggest that KPT-330 enhances crosstalk between these signaling pathways and will therefore test the overall hypothesis that: KPT-330 is a novel, therapeutic drug that treats CAVD by preventing nuclear export of NFAT5 and inhibiting osteogenic markers by increasing Sox9 and repressing Wnt. To test this we will address the following three specific aims: 1) Determine the therapeutic window of KPT-330 administration in the treatment of CAVD in vivo;; 2) Delineate the mechanism of KPT-330 mediated treatment of CAVD through NFAT5 signaling;; and 3) Determine if NFAT5 loss of function is sufficient to cause CAVD in vivo. Upon completion we will have determined the therapeutic potential of a Phase III clinical compound, KPT-330 in the treatment of CAVD, and delineated the mechanisms underlying its function via a novel, NFAT5-mediated signaling pathway. Together, these studies address the purpose of this basic research in CAVD RFA and findings could lead to a new effective medical therapy for this common disorder.

项目总结

项目成果

期刊论文数量（7）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Temporal Progression of Aortic Valve Pathogenesis in a Mouse Model of Osteogenesis Imperfecta.

DOI：
10.3390/jcdd10080355
发表时间：
2023-08-20
期刊：
Journal of cardiovascular development and disease
影响因子：
2.4
作者：
通讯作者：

Genetic and Developmental Contributors to Aortic Stenosis.

DOI：
10.1161/circresaha.120.317978
发表时间：
2021-04-30
期刊：
Circulation research
影响因子：
20.1
作者：
Dutta P;James JF;Kazik H;Lincoln J
通讯作者：
Lincoln J

Smooth Muscle α-Actin Expression in Mitral Valve Interstitial Cells is Important for Mediating Extracellular Matrix Remodeling.

DOI：
10.3390/jcdd7030032
发表时间：
2020-08-19
期刊：
Journal of cardiovascular development and disease
影响因子：
2.4
作者：
Dye BK;Butler C;Lincoln J
通讯作者：
Lincoln J

The Genetic Regulation of Aortic Valve Development and Calcific Disease.

DOI：
10.3389/fcvm.2018.00162
发表时间：
2018
期刊：
Frontiers in cardiovascular medicine
影响因子：
3.6
作者：
Menon V;Lincoln J
通讯作者：
Lincoln J

KPT-330 Prevents Aortic Valve Calcification via a Novel C/EBPβ Signaling Pathway.

DOI：
10.1161/circresaha.120.318503
发表时间：
2021-04-30
期刊：
Circulation research
影响因子：
20.1
作者：
Dutta P;Kodigepalli KM;LaHaye S;Thompson JW;Rains S;Nagel C;Thatcher K;Hinton RB;Lincoln J
通讯作者：
Lincoln J