Project 2 - Molecular Imaging of ectopic calcification

项目2总结 异位钙化的分子成像。钙化的不溶性沉积物的形成不仅仅是 旁观者或副现象，但在老年性黄斑变性的病理中起关键作用 老年痴呆症(AMD)和阿尔茨海默病(AD)，可能还有其他与衰老有关的疾病。眼睛中的钙沉积 在Bruch膜和视网膜色素上皮之间有核形成长玻璃体， 与AMD相关，在某些情况下预测进展为晚期疾病。此外，在AD患者的大脑中， 观察到磷酸化的Tau与神经元内的钙化有关。了解 这些疾病的钙化过程受到现有荧光染色的限制， 尤其是为了研究这些疾病的活体动物模型组织中钙化的发展， 尤其是在视网膜外。而计算机断层扫描(CT)、正电子发射等技术 体层摄影术(PET)和磁共振成像(MRI)都能提供良好的组织穿透性，它们只提供 最好的分辨率为毫米，并具有适度的特异性。该项目的主旨是开发改进的 发光传感器克服了现有传感器的缺点。特别是，我们将发展 传感器具有可调的选择性和动力学，改变了转导(反应)，并提高了靶向性， 允许检测到微小的钙化，即使在灌流组织的深处也是如此。这些新型传感器将是 提供给我们的项目，使他们能够在细胞、组织和活着中进行前所未有的实验 AMD、AD等疾病的动物模型。特别是，我们将开发传感器来研究连续的 假性黄瘤等异位钙化性疾病动物模型中钙化的研究进展 婴儿的弹性动脉(PXE)和泛发性动脉钙化(GACI) 区分不同的钙化化学形式。我们还将开发用于后续钙化的传感器 细胞和亚细胞细胞器。我们在这个项目中的目标不仅仅是开发更好的工具来阐明 细胞和活体动物模型中的钙化过程，也是为了识别和测试新的治疗方法 接近了。我们注意到，其他表现为钙化表型的疾病，如动脉粥样硬化、心脏 瓣膜病和乳腺癌也可能从这些发展中受益。

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.