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.
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
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