Osteopontin: a Novel Biomarker for Calcific Aortic Valve Diseases

描述(由申请人提供)： 这项申请涉及广泛的领域(03)-生物标记物的发现和验证，以及特定的挑战主题03-HL-101：识别和验证血液、血管、心脏和呼吸道功能障碍的诊断和治疗反应的临床相关、可量化的生物标记物。项目标题：骨桥蛋白：钙化性主动脉瓣疾病的新生物标志物主动脉瓣钙化是一个多因素的过程，与各种潜在的相关病理有关。尽管与主动脉瓣钙化相关的发病率和死亡率很高，但对其发病机制知之甚少。我们提出了一项为期两年的转译研究，以验证和表征血液和组织来源的骨桥蛋白作为瓣膜钙化的生物标志物。骨桥蛋白(OPN)是一种多功能糖磷蛋白，参与调节营养不良和异位部位的生理性钙化和生物矿化。令人惊讶的是，尽管OPN在体外和体内都能抑制钙化，但在钙化瓣膜病患者的心脏瓣膜中发现OPN水平升高。所有现有的研究都局限于对瓣膜钙化过程中OPN的定量评估。在知情同意后，血液和组织样本将从有钙性主动脉瓣病征兆的患者和年龄和性别匹配的对照组中收集。骨桥蛋白和RNA将被提纯。分离的OPN和/或不同的OPN剪接变异体的翻译后修饰(S)的特征可能有助于深入了解OPN在主动脉瓣钙化发病机制中的功能作用(S)。这种洞察力可以用来开发瓣膜钙化程度和进展的预测指标(S)，并确定这种普遍和重要疾病的潜在治疗靶点。钙化性主动脉瓣狭窄患者的循环和瓣膜相关OPN的生物学活性的特征从未被进行过。我们提出的这项研究可以为确定治疗靶点做出重大贡献，这些靶点不仅有利于钙化性主动脉瓣疾病患者，也有利于导致主动脉瓣组织结构退化的其他病理疾病的患者。这项研究还将通过直接创造新的就业机会以及直接和间接保留其他就业机会，为该区域带来直接的经济利益。 公共卫生相关性： 主动脉瓣钙化是多种相关病理基础下的多因素过程。由于与主动脉瓣钙化相关的高患病率和高死亡率，人们经常需要新的生物标志物来早期诊断这种疾病。我们提出了一项转译研究，旨在将组织和血液来源的骨桥蛋白作为预测主动脉瓣钙化程度和进展的指标。

DESCRIPTION (provided by applicant): This application addresses broad area (03) - Biomarkers Discovery and Validation and the specific challenge topic, 03-HL-101: Identify and validate clinically relevant, quantifiable biomarkers of diagnostic and therapeutic responses for blood, vascular, cardiac, and respiratory tract dysfunction. Project Title: Osteopontin: a Novel Biomarker for Calcific Aortic Valve Diseases The calcification of the Aortic Valve represents a multifactorial process with varied underlying associated pathologies. Despite the high prevalence and mortality associated with aortic valve calcification, little is known about its pathogenetic mechanisms. We propose a two-year translational research study to validate and characterize blood- and tissue- derived Osteopontin as a biomarker of valvular calcification. Osteopontin (OPN) is a multifunctional glyco-phospho-protein implicated in the regulation of both physiological calcification and biomineralization of dystrophic and ectopic sites. Surprisingly, although OPN inhibits calcification both in vitro and in vivo, elevated levels of OPN have been found in the heart valves of patients with calcified valvular disease. All available studies have been limited to the quantitative assessment of OPN during valvular calcification. Upon informed consent, blood and tissue specimens will be collected from patients with signs of Calcific Aortic Valve Disease and from age- and gender-match controls. Osteopontin protein and RNA will be purified. The characterization of post-translational modification(s) of isolated OPN and/or the different Opn splicing variants may provide insight to the functional role(s) of OPN in the pathogenesis of Aortic Valve Calcification. Such insights can be used to develop predictor(s) for the degree and progression of valvular calcification and to identify potential therapeutic targets for this prevalent and significant disease. RELEVANCE The characterization of the biological activity of circulating and valve-associated OPN from patients with calcific aortic valve stenosis has never been performed. The study we propose can bring a significant contribution to the identification of therapeutic targets that will benefit patients not only with Calcific Aortic Valve Diseases but also with other pathologies leading to structural degeneration of aortic valve tissue. The study will also provide an immediate economic benefit to the region with the direct creation on new jobs and the direct and indirect retain of others. Public Health Relevance: The calcification of the aortic valve represents a multifactor process underling varied associated pathologies. Due to the high prevalence and mortality associated with aortic valve calcification novel biomarkers are constantly needed for an early diagnosis of the disease. We propose a translational research study aim to characterize tissue- and blood-derived osteopontin as a predictor for the degree and progression of aortic valve calcification