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Basic Mechanisms of Human Calcific Aortic Valve Disease

人类钙化性主动脉瓣疾病的基本机制

基本信息

批准号：
8353051
负责人：
Lauren D. Black III
金额：
$ 40.76万
依托单位：
TUFTS MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-08-23 至 2016-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8353051
关键词：
AXIN1 gene Adverse drug effect Affect Animals Awareness Bicuspid Biological Biological Testing Biology Blood CDH13 gene Cadherins Calcified Calcium Candidate Disease Gene Cell Communication Cells Characteristics Congenital Heart Defects Cyclin-Dependent Kinases Data Set Deposition Development Disease Echocardiography Elderly Endoglin Engineering Extracellular Matrix Framingham Heart Study Gene Expression Profile Genes Genetic Genetic Polymorphism Genetic Variation Growth Heart Heart Valve Diseases Human Human Genetics Life Measures Medical Modeling Mus Mutation Nucleotides Operative Surgical Procedures Osteogenesis Pathway Analysis Pathway interactions Patients Phenotype Phosphorylation Physiologic calcification Population Property Qualifying RNA RNA Splicing Regulation Research Retinoblastoma Protein Role Signal Pathway Signal Transduction Single Nucleotide Polymorphism Stem cells Stenosis Stimulus Surveys Testing Therapeutic Tissues Transcript Translating Variant Work abstracting aortic valve aortic valve disorder bone calcification cell growth regulation disease phenotype experience gain of function genetic analysis genome wide association study genome-wide insight interstitial cell loss of function mutation mineralization mouse model notch protein osteogenic osteoprogenitor cell prevent programs promoter response soft tissue transcription factor valve replacement

项目摘要

DESCRIPTION (provided by applicant): Progressive calcific aortic valve disease (CAVD) is characterized by calcium deposition in the valve cusps as well as frank bone formation. People born with a bicuspid aortic valve (BAV), a common congenital heart defect, can develop significant CAVD during the prime of life. BAV and CAVD are regulated by genetic factors including mutations in the Notch1 gene. We analyzed human genetic datasets to identify gene variants associated with BAV and/or CAVD. Our genetic analysis of the Tufts BAV Genetics Study identified gene variants in the WNT/b-catenin and TGFb signaling pathways, which are known to contribute to aortic valve development as well as valve calcification. Our unpublished genome-wide association analysis of the Framingham Heart Study has further identified gene variants in the cyclin dependent kinase (CDK), the soft tissue calcification and the cell-cell communication pathways associated with CAVD. The association of CDK7 gene SNPs with aortic valve calcification is provocative because we have previously demonstrated that the retinoblastoma protein (pRb) and CDK pathway regulate bone formation through the runx2 transcription factor and by regulating cellular responses to Notch1. Taken together we put forth an over-arching hypothesis that the pRb-CDK pathway regulates CAVD through transcriptional effects on soft tissue calcification and cell-cell communication genes regulated by runx2 and Notch1. We will test this hypothesis in our first specific aim by comparing pRb-deficient and control valve interstitial cell (VIC) growh and expression of bone and calcification gene markers in response to factors that stimulate mineralization. Next, we will compare pRb-deficient and control VIC extracellular matrix stiffness characteristics and calcification. Finally we will determine whether pRb regulates runx2 occupancy of soft tissue calcification gene promoters in VICs. In our second aim we will study mice engineered to have a loss- or a gain-of-function in CDK6 that have significant bone and mineralization phenotypes. Further, we will define the role of cdk6 in regulation of VIC osteogenic responses to Notch, and we will survey pRb-cdk mouse models for aortic valve calcification. In our third aim we will analyze expression and activity of pRb-cdk components in human calcified aortic valve tissue. Finally, to broadly survey expression of the pRb-cdk pathway, as well as genes that regulate soft-tissue calcification and cell-cell communication, we will sequence the CAVD transcriptome (RNA-seq). We have assembled a team of experts with experience in CAVD genetics, the regulation of the osteogenic transcriptional program and calcification by the pRb-CDK pathway, and the heart extracellular matrix. We anticipate that our studies will provide unique insights to the biology of CAVD and that this work will translate meaningfully to the understanding of calcific aortic valve disease as well as help guide potential therapeutic options or raise awareness of potential adverse drug effects on the aortic valve. (End of Abstract)

描述（由申请人提供）：