OVERALL SUMMARY Molecular mechanisms of calcification: roles and opportunities in diseases of aging. Ectopic calcification is a hallmark of major diseases of aging, including Age-Related Macular Degeneration (AMD) and Alzheimer's Disease (AD), disorders that each represent the leading causes of central vision loss and dementia among the aging population worldwide, and are currently incurable. There is an urgent need to understand disease mechanisms to enable the development of effective treatments. The overall goal of this Program Project is to elucidate the biological mechanisms of ectopic calcification and its role in the onset and etiology of diseases of aging, with particular focus on age-related macular degeneration (AMD) and Alzheimer’s disease (AD). The major components of the ectopic calcifications in AMD and AD are proteins, lipids and mineralized calcium phosphate, especially in the form of hydroxyapatite (HAP) and whitlockite (WHT), but the roles of these components in the calcification process and disease progression are not known. Four Projects, an administrative Core and a technical Core, will synergize to investigate ectopic calcification at the molecular, cellular and organismal levels, and build a comprehensive view of the key molecules and pathways responsible for this aging-related phenomenon. There are three overall Goals: (1) Elucidate the molecular mechanisms of ectopic calcification; (2) Develop diagnostic sensors for ectopic calcification; and (3) Dissect intra- and extra-cellular factors of ectopic calcification. The primary role of administrative Core will be to facilitate interactions among the investigators to generate a comprehensive view of calcification that could not be achieved by individual laboratories working alone.