Aortic valve microcalcification

描述(由申请人提供)： 本研究项目将验证这一假设，即在糖尿病环境中，S100A9诱导瓣膜间质细胞(VIC)来源的基质小泡的钙化潜力，该基质小泡是微钙化的前体，为钙化性主动脉瓣病(CAVD)提供新的机制。我们的初步研究表明，S100A9--一种最近发现的急性心血管事件的生物标志物--由VIC和基质小泡的一种成分表达。本研究将在体内和体外研究S100A9和基质囊泡在糖尿病患者主动脉瓣钙化中的相互作用。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。我们发表的研究将炎症和钙化联系在一起，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。特定目的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说。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、微钙化和CAVD。特定目标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。特异靶3将在体外研究S100A9介导的钙化基质囊泡形成的机制。这些互补性研究将通过确定S100A9在微钙化中的作用来推动该领域的发展。该项目的发现将支持S100A9作为CAVD的治疗靶点。此外，这个项目 将为开展大型动物和人类患者CAVD早期诊断的影像学研究提供依据。 (摘要结束)

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)