Aortic valve microcalcification

主动脉瓣微钙化

基本信息

批准号：
8535816
负责人：
Elena Aikawa
金额：
$ 39.58万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
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 2017-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8535816
关键词：
Acute Address Affect Aging Animal Model Animals Apolipoprotein E Arteries Biological Markers Breast Microcalcification Calcified Calcium Calcium-Binding Proteins Cardiovascular system Cell Count Cell Culture Techniques Cell membrane Cell surface Cells Clinic Complications of Diabetes Mellitus Data Deposition Detection Development Diabetes Mellitus Diabetic mouse Early Diagnosis Early treatment Event Genetic Goals Histology Human Image Imaging Techniques Imaging technology In Vitro Incidence Inflammation Inflammatory Intervention Link Mediating Molecular Morbidity - disease rate Mus National Heart, Lung, and Blood Institute Optical Coherence Tomography Patients Phenotype Pilot Projects Process Production Proteomics Publishing Research Project Grants Resolution Role S100A9 gene Serum Shapes Small Interfering RNA Societies Spatial Distribution Specimen Testing Therapeutic Therapeutic Intervention United States Vesicle Work abstracting aortic valve aortic valve disorder base calcification diabetic global health imaging modality in vivo interstitial cell macrophage mineralization molecular dynamics molecular imaging mortality mouse model new therapeutic target novel pre-clinical repaired research study therapeutic target tool translational study valve replacement

项目摘要

DESCRIPTION (provided by applicant): This research project will test the hypothesis that, in the diabetic milieu, S100A9 induces the calcification potential of valvular interstitial cell (VIC)-derived matrix vesicles, precursors of microcalcification, offering the novel mechanism of calcific aortic valve disease (CAVD). Our pilot studies showed that S100A9 - a recently identified biomarker of acute cardiovascular events - is expressed by VIC and a component of matrix vesicles. The present study will examine in vivo and in vitro the role of interplay between S100A9 and matrix vesicles in aortic valve calcification in diabetes. A lack of high-resolution imaging techniques that can detect preclinical microcalcification is a critical barrier to the treatment of CAVD. Our published studie linked inflammation and calcification and showed that molecular imaging and micro-optical coherence tomography (¿OCT) can identify microcalcification undetectable by other imaging modalities. Specific Aim 1 will test the hypothesis in vivo that S100A9 promotes the formation of microcalcification in aortic valves of diabetic mice. We expect that genetic deletion of S100A9 will reduce diabetes-triggered matrix vesicle release, microcalcification, and CAVD. Specific Aim 2 will develop novel imaging to evaluate quantitatively the impact of microcalcification on CAVD in diabetic mice and humans. Specific Aim 3 will examine in vitro S100A9-mediated mechanisms for the formation of calcifying matrix vesicles. These complementary studies will advance the field by identifying the role of S100A9 in microcalcification. The findings from this project will bolster support for S100A9 as a therapeutic target for CAVD. In addition, this project will provide bases for the development of imaging for early diagnosis of CAVD in large animals and human patients. (End of Abstract)

描述（由申请人提供）：该研究项目将测试以下假设：在糖尿病环境中，S100A9 会诱导瓣膜间质细胞 (VIC) 衍生的基质囊泡（微钙化的前体）的钙化潜力，从而提供钙化主动脉瓣疾病 (CAVD) 的新机制。研究表明，S100A9（最近发现的一种急性心血管事件生物标志物）由 VIC 表达，也是基质囊泡的一个组成部分。本研究将在体内和体外研究 S100A9 和基质囊泡之间的相互作用在糖尿病主动脉瓣钙化中的作用。缺乏能够检测临床前微钙化的高分辨率成像技术是治疗 CAVD 的关键障碍。发表的研究将炎症和钙化联系起来，并表明分子成像和微光学相干断层扫描（OCT）可以识别其他成像方式无法检测到的微钙化。具体目标 1 将在体内验证 S100A9 促进糖尿病小鼠主动脉瓣微钙化形成的假设，我们预计 S100A9 的基因缺失将减少糖尿病引发的基质囊泡释放、微钙化，并且 CAVD 将开发新的。具体目标 3 将在体外检查微钙化对糖尿病小鼠和人类 CAVD 的影响。 S100A9 介导的钙化基质囊泡形成机制将通过确定 S100A9 在微钙化中的作用来推动该领域的发展。此外，该项目将支持 S100A9 作为 CAVD 的治疗靶点。将为大型动物和人类患者的 CAVD 早期诊断成像技术的发展提供基础。（摘要完）