Aortic valve microcalcification

描述（由申请人提供）： 本研究项目将验证以下假设：在糖尿病环境中，S100 A9诱导瓣膜间质细胞（维克）衍生的基质囊泡（微钙化的前体）的钙化潜能，提供钙化性主动脉瓣疾病（CAVD）的新机制。我们的初步研究表明，S100 A9-最近确定的急性心血管事件的生物标志物-由维克和基质囊泡的组分表达。本研究将在体内和体外研究S100 A9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CAVD治疗的关键障碍。我们发表的研究将炎症和钙化联系起来，并表明分子成像和显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将在体内检验S100 A9促进糖尿病小鼠主动脉瓣微钙化形成的假设。我们预期S100 A9基因缺失将减少糖尿病引发的基质囊泡释放、微钙化和CAVD。Specific Aim 2将开发新的成像技术，以定量评估微钙化对糖尿病小鼠和人类CAVD的影响。具体目标3将检查体外S100 A9介导的钙化基质囊泡形成机制。这些补充研究将通过确定S100 A9在微钙化中的作用来推进该领域。该项目的发现将支持S100 A9作为CAVD的治疗靶点。此外，该项目 为大动物和人类CAVD的早期诊断提供影像学基础。 (End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)