Project 2 - Molecular Imaging of ectopic calcification

项目 2 - 异位钙化的分子成像

• 批准号: 10628929
• 负责人: RICHARD Blair THOMPSON
• 金额: $ 45.06万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2028-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10628929
• 关键词: Age related macular degeneration; Aging; Alzheimer' s Disease; Alzheimer' s disease brain; Animal Disease Models; Animal Model; Animals; Atherosclerosis; Baltimore; Binding; Bioluminescence; Biosensor; Brain; Bruch' s basal membrane structure; Calcium; Cells; Chemicals; Clinical; Complex; Deposition; Detection; Development; Disease; Drusen; Early Diagnosis; Early identification; Energy Transfer; Exhibits; Eye; Family; Fluorescence; Fluorescence Anisotropy; Goals; Heart Valve Diseases; Hemopexin; Histology; Hydroxyapatites; Image; Immobilization; Immunity; In Vitro; Ions; Kinetics; Label; Light; Lipids; Magnetic Resonance Imaging; Maryland; Metals; Microscopic; Minerals; Modeling; Molecular; Monitor; Neurons; Optics; Organelles; Pathologic; Pathology; Penetration; Perfusion; Phase; Phenotype; Play; Positron-Emission Tomography; Probability; Process; Protein Family; Proteins; Pseudoxanthoma Elasticum; Reporting; Research; Resolution; Retina; Role; Signal Transduction; Solid; Specificity; Stains; Structure of retinal pigment epithelium; Techniques; Testing; Time; Tissues; Universities; Vitronectin; X-Ray Computed Tomography; advanced disease; aging population; animal tissue; arterial calcification of infancy; calcification; carbonate dehydratase; cohort; design; early detection biomarkers; experimental study; fluorescence imaging; fluorophore; high throughput screening; improved; in vivo; malignant breast neoplasm; millimeter; molecular imaging; multi-photon; nonhuman primate; novel; novel therapeutic intervention; programs; protein function; protein structure; response; sensor; sensor technology; small molecule; tau-1; therapeutic target; tool

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.

项目 2 总结 异位钙化的分子成像 钙化、不溶性沉积物的形成不仅仅是一种现象。 旁观者或附带现象，而是在年龄相关性黄斑变性的病理学中起着关键作用 （AMD）和阿尔茨海默病（AD），以及可能的其他眼部钙沉积疾病。 布鲁赫膜和视网膜色素上皮细胞之间形成玻璃膜疣，长 与 AMD 相关，并且在某些情况下预测 AD 大脑进展为晚期疾病， 观察到磷酸化 Tau 与神经元细胞内钙化相关。 这些疾病的钙化过程受到现有荧光染色剂局限性的阻碍， 特别是研究这些疾病的活体动物模型组织中钙化的发展， 尤其是在视网膜之外。而计算机断层扫描 (CT)、正电子发射等技术 断层扫描 (PET) 和磁共振成像 (MRI) 都提供良好的组织穿透性，但它们仅提供 最好是毫米分辨率，并且具有适度的特异性。该项目的主旨是开发改进的。 我们将特别开发克服现有传感器缺点的发光传感器。 具有可调选择性和动力学、改变的转导（响应）和改进的靶向性的传感器， 这些新型传感器甚至可以检测灌注组织深处的微小钙化。 提供给我们的项目，使他们能够在细胞、组织和活体中进行前所未有的实验 特别是，我们将开发AMD、AD和其他疾病的动物模型来研究连续性。 异位钙化疾病（如假黄瘤）动物模型中钙化的发展 Elasticum (PXE) 和婴儿全身动脉钙化 (GACI)，能够通过光学方式 我们还将开发用于跟踪钙化的传感器。 我们在这个项目中的目标不仅仅是开发改进的工具来阐明。 细胞和活体动物模型中的钙化过程，还可以识别和测试新的疗法 我们注意到其他表现出钙化表型的疾病，如动脉粥样硬化、心脏疾病。 瓣膜疾病和乳腺癌也可能受益于这些发展。