Project 2 - Molecular Imaging of ectopic calcification

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PROJECT 2 SUMMARY Molecular Imaging of Ectopic Calcification. The formation of calcified, insoluble deposits is not just a bystander or epiphenomenon, but rather plays key roles in the pathology of Age-related Macular Degeneration (AMD) and Alzheimer's Disease (AD), and probably other diseases of aging. Calcium deposits in the eye between the Bruch’s membrane and the retinal pigment epithelium nucleate the formation of drusen, long associated with AMD, and in some cases predict progression to advanced disease. Moreover in AD brains, phosphorylated Tau is observed associated with intracellular calcification in neurons. Understanding the calcification processes in these diseases has been hampered by the limitations of existing fluorescent stains, particularly for studying the development of calcification in the tissues of live animal models of these diseases, especially outside the retina. While techniques like computed tomography (CT), Positron Emission Tomography (PET), and magnetic resonance imaging (MRI) all offer good tissue penetration, they offer only millimeter resolution at best, and modest specificity. The thrust of this Project is to develop improved luminescent sensors that overcome the shortcomings of the existing sensors. In particular, we will develop sensors with tunable selectivity and kinetics, altered transduction (response), and improved targetability, that permit detection of microscopic calcification even deep in perfused tissue. These novel sensors will be supplied to our Projects to enable them to carry out unprecedented experiments in cells, tissues, and live animal models of AMD, AD, and other diseases. In particular, we will develop sensors to study the continuous development of calcification in animal models of ectopic calcification diseases such as Pseudoxanthoma Elasticum (PXE) and Generalized Arterial Calcification of Infancy (GACI), that are capable of optically distinguishing different chemical forms of calcification. We also will develop sensors for following calcification in cells and subcellular organelles. Our goals in this Project are not only to develop improved tools to elucidate the calcification processes in cellular and live animal models, but also to identify and test new therapeutic approaches. We note that other diseases exhibiting calcification phenotypes such as atherosclerosis, heart valve disease, and breast cancer, may also benefit from these developments.